VCV000128042.130 - ClinVar

NM_007194.4(CHEK2):c.1100del (p.Thr367fs)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(81)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_007194.4(CHEK2):c.1100del (p.Thr367fs)

Variation ID: 128042 Accession: VCV000128042.130

Type and length

Deletion, 1 bp

Location

Cytogenetic: 22q12.1 22: 28695869 (GRCh38) [ NCBI UCSC ] 22: 29091857 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 19, 2014	Oct 20, 2024	Sep 30, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_007194.4:c.1100del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_009125.1:p.Thr367fs	frameshift
NM_007194.4:c.1100delC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001005735.1:c.1229del
NM_001005735.2:c.1229del	NP_001005735.1:p.Thr410fs	frameshift
NM_001005735.2:c.1229delC
NM_001257387.2:c.437del	NP_001244316.1:p.Thr146fs	frameshift
NM_001349956.2:c.899del	NP_001336885.1:p.Thr300fs	frameshift
NM_145862.2:c.1013del	NP_665861.1:p.Thr338fs	frameshift
NC_000022.11:g.28695869del
NC_000022.10:g.29091857del
NG_008150.2:g.50998del
LRG_302:g.50998del
LRG_302t1:c.1100del	LRG_302p1:p.Thr367fs

... more HGVS ... less HGVS

Protein change

T146fs, T338fs, T410fs, T300fs, T367fs

Other names

NP_009125.1:p.Thr367MetfsTer15

Canonical SPDI

NC_000022.11:28695868:G:

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Uncertain function

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00100 ()

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 30x 0.00109

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00120

The Genome Aggregation Database (gnomAD) 0.00181

Exome Aggregation Consortium (ExAC) 0.00182

The Genome Aggregation Database (gnomAD), exomes 0.00204

1000 Genomes Project 0.00100

Trans-Omics for Precision Medicine (TOPMed) 0.00100

Links

ClinGen: CA288251 OMIM: 604373.0001 dbSNP: rs555607708 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
CHEK2		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	4053	4109

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Li-Fraumeni syndrome 2	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Aug 9, 2024	RCV000005932.21
Hereditary cancer-predisposing syndrome	Pathogenic (10)	criteria provided, multiple submitters, no conflicts	Apr 11, 2023	RCV000115980.33
Familial cancer of breast	Pathogenic (14)	criteria provided, multiple submitters, no conflicts	Sep 30, 2024	RCV000123265.48
Breast and colorectal cancer, susceptibility to	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Nov 20, 2015	RCV000210137.14
not provided	Pathogenic (20)	criteria provided, multiple submitters, no conflicts	Jul 31, 2024	RCV000212447.82
Breast neoplasm	Pathogenic (1)	criteria provided, single submitter	-	RCV000413386.9
Breast cancer, susceptibility to	Pathogenic (1)	no assertion criteria provided	Nov 22, 2021	RCV000500025.16
Breast neoplasm Leiomyosarcoma	Pathogenic (1)	no assertion criteria provided	-	RCV000488416.9
Bone osteosarcoma Familial cancer of breast Li-Fraumeni syndrome 2 Malignant tumor of prostate	Pathogenic (1)	criteria provided, single submitter	May 18, 2017	RCV000515188.10
Li-Fraumeni syndrome	Pathogenic (1)	criteria provided, single submitter	Jul 25, 2019	RCV000587467.10
Astrocytoma	no classifications from unflagged records (1)	no classifications from unflagged records	Aug 9, 2022	RCV000591014.10
Colitis Hematochezia Inflammation of the large intestine Thrombocytopenia	Pathogenic (1)	criteria provided, single submitter	-	RCV000735378.10
Breast and/or ovarian cancer	Pathogenic (2)	criteria provided, single submitter	May 7, 2021	RCV001270933.11
Carcinoma of pancreas	Pathogenic (1)	no assertion criteria provided	Mar 4, 2021	RCV001391208.9
Malignant tumor of breast	Pathogenic (1)	no assertion criteria provided	-	RCV001354431.10
Breast carcinoma	Pathogenic (1)	no assertion criteria provided	Aug 19, 2021	RCV001572630.9
Bone osteosarcoma	Pathogenic (1)	no assertion criteria provided	Jul 26, 2021	RCV001770086.10
Hereditary breast ovarian cancer syndrome	Pathogenic (1)	criteria provided, single submitter	Apr 19, 2022	RCV002225332.9
Colorectal cancer	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jun 9, 2023	RCV002463641.10
Colorectal cancer Familial cancer of breast Malignant tumor of prostate	Pathogenic (1)	criteria provided, single submitter	Sep 26, 2022	RCV002285140.8
Predisposition to cancer	Pathogenic (1)	criteria provided, single submitter	May 24, 2022	RCV002291559.8
Li-Fraumeni syndrome 1	Pathogenic (1)	criteria provided, single submitter	Oct 26, 2023	RCV003388828.1
Ovarian neoplasm	Pathogenic (1)	no assertion criteria provided	Jul 28, 2023	RCV003445511.1
TUMOR PREDISPOSITION SYNDROME 4, BREAST/PROSTATE/COLORECTAL	Pathogenic (1)	no assertion criteria provided	Nov 1, 2006	RCV003333692.1
Malignant tumor of prostate	Pathogenic (1)	criteria provided, single submitter	Mar 15, 2024	RCV003992185.1
CHEK2-related disorder	Pathogenic (1)	no assertion criteria provided	Sep 27, 2024	RCV004528801.3
CHEK2-related cancer predisposition	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Apr 27, 2017	RCV004556721.1
Inherited breast cancer and ovarian cancer	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jun 14, 2024	RCV004577323.2
Breast-ovarian cancer, familial, susceptibility to, 1	Pathogenic (1)	criteria provided, single submitter	Aug 22, 2024	RCV004760381.1
NICE approved PARP inhibitor treatment	Pathogenic (1)	criteria provided, single submitter	Aug 12, 2024	RCV004691754.1
click to load more click to collapse

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Oct 04, 2021)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002537022.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 Comment: The CHEK2 c.1100delC (p.T367MfsX15) variant is a well-known pathogenic variant associated with increased risk for breast, colorectal and prostate cancer. This variant was observed in … (more) The CHEK2 c.1100delC (p.T367MfsX15) variant is a well-known pathogenic variant associated with increased risk for breast, colorectal and prostate cancer. This variant was observed in 219/25124 chromosomes in the Finnish population, with 1 homozygote, in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variant ID 128042). Meta-analysis including 118,735 breast cancer cases and 195,807 controls indicated an increased breast cancer risk in overall populations (OR 2.89; 95% CI 2.63-3.16) (PMID: 29909568). Similar meta-analysis studies have shown a modest increase in colorectal (OR 1.88, 95% CI 1.29-2.73) and prostate (OR 1.98, 95% CI 1.23-3.18) cancer risk (PMID: 25431674, 23946381). This variant has also been found associated with an increased risk for other cancer types including thyroid and melanoma (PMID: 25583358, 21956126). This variant causes a frameshift at amino acid 367 that results in premature termination 15 amino acids downstream. At this location, this is predicted to result in absent protein (loss of function). Loss-of-function variants in CHEK2 are known to be pathogenic. Functional studies have shown that this variant displayed no kinase activity in vitro (PMID: 11719428). Based on the current evidence available, this variant is interpreted as pathogenic with reduced penetrance. (less)	Publications: PubMed (6) PubMed: 29909568‚ 25431674‚ 23946381‚ 25583358‚ 21956126‚ 11719428
Pathogenic (Aug 24, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002581843.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PVS1, PS3_MOD, PS4_SUP	Number of individuals with the variant: 23 Sex: male
Pathogenic (Jun 09, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Colorectal cancer (Autosomal dominant inheritance) Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV004027697.1 First in ClinVar: Aug 26, 2023 Last updated: Aug 26, 2023	Comment: Criteria applied: PVS1,PS3,PS4,PM2_SUP Clinical Features: Family history of cancer (present) Sex: male
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	SUSCEPTIBILITY TO BREAST AND COLORECTAL CANCER Affected status: yes Allele origin: germline	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Accession: SCV004046245.1 First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023	Comment: This variant is also referred to as c.1100delC (p.Thr367MetfsTer15) (NM_007194.3) in the literature. This deletion in exon 12 of 16 causes a frameshift and a … (more) This variant is also referred to as c.1100delC (p.Thr367MetfsTer15) (NM_007194.3) in the literature. This deletion in exon 12 of 16 causes a frameshift and a premature stop codon at residue 424 and is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). The c.1229del (p.Thr410MetfsTer15) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.2% (585/275092) and is present in the homozygous state at a frequency of 0.0004% (1/275092). This variant is enriched in the European (Finnish) population (MAF=0.87%). Based on two large case-control studies, the relative risk for female breast cancer associated with the c.1229del variant was 3.0 (90% CI, 2.6-3.5) (PMID: 26014596, 15122511, 23109706). Additionally, a meta-analysis reported a relative risk of 1.88 (95% C.I. 1.29-2.73) for colorectal cancer associated with the c.1229del variant (PMID: 23946381). The c.1229del variant has also been associated with an increased risk of prostate cancer (PMID: 26629066) and other cancers (PMID: 26884562, 21956126). Based on the available evidence, the c.1229del (p.Thr410MetfsTer15) variant is classified as Pathogenic. (less)
Pathogenic (Oct 26, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Li-Fraumeni syndrome 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV004100720.1 First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023	Comment: Criteria applied: PVS1,PS3,PS4 Clinical Features: Breast carcinoma (present) Sex: female
Pathogenic (May 04, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000691834.3 First in ClinVar: Feb 19, 2018 Last updated: Jan 26, 2024	Comment: PP5, PS4_moderate, PVS1 Number of individuals with the variant: 27
Pathogenic (Apr 11, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000292118.5 First in ClinVar: Jul 08, 2016 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 18172190‚ 21807500‚ 22994785‚ 28135145‚ 28734145 Comment: This variant deletes 1 nucleotide in exon 11 of the CHEK2 gene, creating a frameshift and premature translation stop signal. This variant is expected to … (more) This variant deletes 1 nucleotide in exon 11 of the CHEK2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. A large meta-analysis of breast cancer case-control studies has determined that female carriers of this variant show a relative risk for familial breast cancer of 4.8 (95% CI: [3.3, 7.2]) and cumulative risk at age 70 years of 37% (95% CI: [26, 56]) vs. 7.8% for the population controls (PMID: 18172190). Another meta-analysis has also shown a significant breast cancer risk in heterozygous carriers of this variant (OR=2.75, 95% CI: [2.25, 3.36]) (PMID: 22994785). The ORs and CIs were 2.33 (95% CI: [1.79, 3.05]), 3.72 (95% CI: [2.61, 5.31]) and 2.78 (95% CI: [2.28, 3.39]), respectively, in unselected, family, early-onset breast cancer subgroups in this study. This variant has been observed in individuals affected with colorectal cancer, but whether this variant is associated with increased risk of colorectal cancer remains uncertain (PMID: 21807500, 28135145, 28734145). This variant is well documented as a breast cancer-associated variant in the literature and in the public database (ClinVar variation ID: 128042). This variant has been identified in 591/280390 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of CHEK2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
Pathogenic (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000166572.15 First in ClinVar: Jun 15, 2014 Last updated: Feb 20, 2024	Publications: PubMed (9) PubMed: 28492532‚ 21876083‚ 24713400‚ 18172190‚ 11967536‚ 14648717‚ 14648718‚ 14648719‚ 15488637 Comment: This sequence change creates a premature translational stop signal (p.Thr367Metfs15) in the CHEK2 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Thr367Metfs15) in the CHEK2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CHEK2 are known to be pathogenic (PMID: 21876083, 24713400). This variant is present in population databases (rs555607708, gnomAD 0.9%), and has an allele count higher than expected for a pathogenic variant. This particular variant has been well described in the literature. In a large meta-analysis comprising 16 studies including 26,488 affected individuals and 27,402 controls, women heterozygous for this variant have a relative risk for familial breast cancer of 4.8 (95% CI, 3.3-7.2). The cumulative risk at age 70 years is 37% (95% CI, 26%-56%), compared to 7.8% for the average Caucasian woman in the general population (PMID: 18172190). Although one study has reported that the c.1100del variant confers an approximate 10-fold increased risk of male breast cancer (PMID: 11967536), the results have yet to be confirmed in further studies (PMID: 14648717, 14648718, 14648719, 15488637). ClinVar contains an entry for this variant (Variation ID: 128042). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Mar 15, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial prostate cancer (Autosomal dominant inheritance) Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV004812116.1 First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024	Comment: Criteria applied: PVS1,PS3,PS4_MOD Clinical Features: Malignant tumor of prostate (present) Sex: male
Pathogenic (Apr 27, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000187220.9 First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024	Publications: PubMed (12) PubMed: 11053450‚ 15122511‚ 18381420‚ 21807500‚ 21956126‚ 22058428‚ 23652375‚ 26884562‚ 27269948‚ 27433846‚ 27751358‚ 28874143 Comment: The c.1100delC (p.T367Mfs15) alteration, located in exon 11 (coding exon 10) of the CHEK2 gene, consists of a deletion of one nucleotide at position 1100, … (more) The c.1100delC (p.T367Mfs15) alteration, located in exon 11 (coding exon 10) of the CHEK2 gene, consists of a deletion of one nucleotide at position 1100, causing a translational frameshift with a predicted alternate stop codon after 15 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Clinic-based studies have estimated an approximately 2-fold increase in female breast cancer, colorectal cancer, and melanoma risk associated with this alteration (CHEK2 Breast Cancer Case-Control, 2004; Xiang, 2011; Weischer, 2012). However, a recent population-based study found a 2-fold increase in female breast cancer risk and 6-fold increase in stomach cancer risk associated with this alteration, but did not find a statistically significant association with colon cancer or melanoma (Näslund-Koch, 2016). Another study found that risk for estrogen receptor (ER) positive breast cancer was more pronounced than risk for ER-negative breast cancer and estimated that the cumulative risks for development of ER-positive and ER-negative tumors by age 80 in carriers were 20% and 3%, respectively, compared with 9% and 2%, respectively, in the general population of the United Kingdom (Schmidt, 2016). This alteration has also been reported in male breast cancer cohorts (Leedom, 2016; Hallamies, 2017), and was identified in 5/692 men with metastatic prostate cancer who were unselected for family history of cancer or age at diagnosis (Pritchard, 2016). This alteration is located within the kinase domain, and is reported to abolish the kinase activity of CHK2 (Wu, 2001). Based on the available evidence, this alteration is classified as pathogenic. (less)
Pathogenic (Aug 22, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV005368410.1 First in ClinVar: Oct 13, 2024 Last updated: Oct 13, 2024	Comment: Criteria applied: PVS1,PS3,PM1 Clinical Features: Breast carcinoma (present) Sex: female
Pathogenic (Apr 30, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Li-Fraumeni syndrome 2 Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV003804673.3 First in ClinVar: Mar 04, 2023 Last updated: Oct 13, 2024	Comment: Criteria applied: PVS1,PS3,PS4 Clinical Features: Breast carcinoma (present) Sex: female
Pathogenic (Sep 30, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast (Autosomal dominant inheritance) Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001429484.6 First in ClinVar: Aug 16, 2020 Last updated: Oct 13, 2024	Comment: Criteria applied: PVS1,PS3,PS4_MOD Clinical Features: Breast carcinoma (present) Sex: female
Pathogenic (Mar 10, 2015)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	CHEK2-Related Cancer Susceptibility (Autosomal dominant inheritance) Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000711416.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018	Publications: PubMed (7) PubMed: 19805189‚ 25431674‚ 21956126‚ 10617473‚ 18172190‚ 21807500‚ 11967536 Comment: The c.1100delC (p.Thr367fs) variant in CHEK2 has been associated with increased risk for several types of cancer, including breast, colorectal, and prostate. Me ta-analyses have … (more) The c.1100delC (p.Thr367fs) variant in CHEK2 has been associated with increased risk for several types of cancer, including breast, colorectal, and prostate. Me ta-analyses have reported an odds ratio of 2-4 for developing breast, colorectal , or prostate cancer, and a possibly smaller increased risk of malignant melanom a (Weischer 2008, Xiang 2011, Weischer 2012, Yang 2012, Wang 2015). In addition, animal models in mice have shown that this variant causes increased tumor forma tion in multiple cancer sites (Bahassi 2009). This variant has also been reporte d by other clinical laboratories in ClinVar (Variation ID 128042). Of note, this variant has been identified in 0.3% (319/125272) of European chromosomes by the genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs 35705950). Therefore, this variant is not expected to cause highly penetrant Men delian disease. In summary, the c.1100delC (p.Thr367fs) variant is an establishe d risk factor for breast, colorectal, and prostate cancers. (less) Number of individuals with the variant: 4
Pathogenic (Jan 26, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Hereditary cancer-predisposing syndrome Affected status: yes Allele origin: germline	Academic Department of Medical Genetics, University of Cambridge Accession: SCV000992228.1 First in ClinVar: Sep 08, 2019 Last updated: Sep 08, 2019 Comment: Identified as part of research study of individuals with multiple primary tumours referred for genetic assessment	Comment: Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity. Observation 1: Clinical Features: Fibrofolliculoma (present) , Clear cell carcinoma of kidney (present) Observation 2: Clinical Features: Adenocarcinoma of the large intestine (present) , Endometrial carcinoma (present) , Basal cell carcinoma (present) Observation 3: Clinical Features: Thyroid carcinoma (present) , Neoplasm of the pancreas (present) Observation 4: Clinical Features: Clear cell carcinoma of kidney (present) , Lymphoma (present) , Adenocarcinoma of the large intestine (present) Observation 5: Clinical Features: Breast carcinoma (present) , Stomach cancer (present) Observation 6: Clinical Features: Endometrial carcinoma (present) , Breast carcinoma (present) Observation 7: Clinical Features: Breast carcinoma (present) , Renal cell carcinoma, papillary, 1 (present) , Neuroendocrine neoplasm (present) , Chronic myelogenous leukemia (present) Observation 8: Clinical Features: Breast carcinoma (present) , Neoplasm of the pancreas (present) Observation 9: Clinical Features: Breast carcinoma (present) Observation 10: Clinical Features: Breast carcinoma (present) , Cutaneous melanoma (present)
Pathogenic (Jul 25, 2019)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Li-Fraumeni syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000698761.2 First in ClinVar: Mar 17, 2018 Last updated: Nov 08, 2019	Publications: PubMed (6) PubMed: 22419737‚ 10617473‚ 15520402‚ 11719428‚ 19338683‚ 28779002 Comment: Variant summary: CHEK2 c.1100delC (p.Thr367MetfsX15) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more) Variant summary: CHEK2 c.1100delC (p.Thr367MetfsX15) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 0.002 in 248982 control chromosomes (gnomAD). Although this variant was found at a relatively high frequency in controls, this is a well-known founder mutation that is known to be relatively frequent in European populations. c.1100delC has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome and also as risk factor for several cancer types (breast, ovarian, prostate, colon, etc.). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated that this variant leads to loss of damage response and kinase activity (Lee_2001, Roeb_2012). Eighteen other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Jan 01, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: yes Allele origin: germline	GeneKor MSA Accession: SCV000821726.2 First in ClinVar: Oct 10, 2018 Last updated: Mar 25, 2020	Comment: This variation is a deletion of 1 nucleotide from exon 11 of the CHEK2 mRNA (c.1100delC), causing a frameshift at codon 367. This creates a … (more) This variation is a deletion of 1 nucleotide from exon 11 of the CHEK2 mRNA (c.1100delC), causing a frameshift at codon 367. This creates a premature translational stop signal 15 amino acid residues later (p.Thr367Metfs*15) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in CHEK2 are known to be pathogenic. This variant has been well described in the literature (PMID: 18172190). The mutation database ClinVar contains an entry for this variant (Variation ID: 128042). (less)
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Unknown mechanism) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001447460.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Breast carcinoma (present) Sex: female
Pathogenic (Jun 14, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Knight Diagnostic Laboratories, Oregon Health and Sciences University Accession: SCV001449028.1 First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020	Number of individuals with the variant: 7
Pathogenic (Jun 04, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics and Genomics, Karolinska University Hospital Accession: SCV001450042.1 First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020	Number of individuals with the variant: 19
Pathogenic (Apr 02, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: yes Allele origin: germline	Department of Molecular Diagnostics, Institute of Oncology Ljubljana Accession: SCV001499790.1 First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021
Pathogenic (Mar 04, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000149889.15 First in ClinVar: May 17, 2014 Last updated: Apr 17, 2019	Comment: Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published … (more) Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect: loss of kinase activity (Lee 2001, Wu 2001); Case control studies suggest this variant is associated with several types of cancer, including breast, colon, prostate, gastric, renal, and thyroid (Seppala 2003, The CHEK2 Breast Cancer Consortium 2004, Cybulski 2006, Desrichard 2011, Teodorczyk 2013, Hale 2014, Ma 2014, Siolek 2015, Naslund-Koch 2016, Schmidt 2016, Couch 2017, Decker 2017, Katona 2017, Carlo 2018); This variant is associated with the following publications: (PMID: 11967536, 14648718, 18759107, 27269948, 14612911, 15122511, 17085682, 22114986, 23296741, 25431674, 23946381, 25583358, 26884562, 28418444, 28779002, 28734145, 29978187, 11719428, 11053450, 31948886, 32832836, 31980526, 32854451, 31263571, 32081490, 31447099, 32255556, 15818573, 32285038, 30777372, 31871297, 30957677, 31206626, 28514723, 31263054, 30877237, 31360903, 30612635, 30303537, 30676620, 30113427, 31159747, 30833417, 31090900, 30309722, 30322717, 29767408, 30623166, 29520813, 29445900, 30947698, 30426508, 29506128, 15095295, 30333958, 28135145, 29909963, 28727877, 25186627, 26556299, 28503720, 28802053, 27806230, 27798748, 28195393, 29489754, 28125075, 19768534, 29351919, 28944238, 29146883, 26332814, 29909568, 28874143, 25980754, 26681312, 22527104, 27083775, 26822237, 27153395, 26084796, 26641009, 27716369, 27488870, 21956126, 27751358, 28008555, 27433846, 27443514, 17661168, 16452051, 15087378, 21807500, 12690581, 14648719, 10617473, 15239132, 22006311, 23409019, 22058428, 23109706, 21876083, 22058216, 20722467, 23415889, 22811390, 19030985, 22520019, 21244692, 22691310, 22994785, 15492928, 23329222, 25835597, 24723567) (less)
Pathogenic (May 07, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast and/or ovarian cancer Affected status: unknown Allele origin: germline	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Accession: SCV002043388.1 First in ClinVar: Jan 01, 2022 Last updated: Jan 01, 2022
Pathogenic (Nov 01, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV002061638.3 First in ClinVar: Jan 22, 2022 Last updated: Aug 05, 2023	Comment: PVS1, PS4, PS3 Secondary finding: yes
Pathogenic (Oct 11, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	AiLife Diagnostics, AiLife Diagnostics Accession: SCV002503454.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Publications: PubMed (5) PubMed: 18172190‚ 22994785‚ 21807500‚ 15087378‚ 21956126 Number of individuals with the variant: 3 Secondary finding: no
Pathogenic (Sep 26, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Familial cancer of breast Colorectal cancer Familial prostate cancer Affected status: unknown Allele origin: unknown	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology Study: COAGS Accession: SCV002575018.1 First in ClinVar: Oct 01, 2022 Last updated: Oct 01, 2022	Comment: PVS1, PS4, PS3_Supporting Number of individuals with the variant: 1
Pathogenic (May 24, 2022)	criteria provided, single submitter (St. Jude Assertion Criteria 2020) Method: clinical testing	Predisposition to cancer Affected status: unknown Allele origin: germline	St. Jude Molecular Pathology, St. Jude Children's Research Hospital Accession: SCV000891024.2 First in ClinVar: Mar 19, 2019 Last updated: Oct 22, 2022	Comment: The CHEK2 c.1100del (p.Thr367MetfsTer15) change causes a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or … (more) The CHEK2 c.1100del (p.Thr367MetfsTer15) change causes a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of the protein due to nonsense mediated decay (PVS1). This variant has been widely reported to be associated with cancer susceptibility, including significant associations with increased risk of breast cancer in large meta-analysis studies (odds ratios ~2-5, PMID: 18172190, 22994785). This variant has also been reported in individuals with colon, prostate, gastric, kidney, and thyroid cancer (PMID: 14612911, 15087378, 15492928, 16880452, 21807500, 23296741, 25431674, 25583358, 26884562). This change has an overall frequency of 0.21% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/) and has been described as a founder variant in Northern European populations (PMID: 15087378). In summary, this variant meets criteria to be classified as pathogenic with evidence indicating lower penetrance. (less)
Pathogenic (Jul 02, 2018)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV000839467.2 First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022
Pathogenic (Oct 27, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002019280.2 First in ClinVar: Nov 29, 2021 Last updated: Mar 11, 2023
Pathogenic (Apr 08, 2022)	criteria provided, single submitter (CanVIG CHEK2 Gene Specific Guidelines V1.0) Method: case-control	Hereditary cancer-predisposing syndrome Affected status: yes Allele origin: germline	Cancer Variant Interpretation Group UK, Institute of Cancer Research, London Accession: SCV003933671.1 First in ClinVar: Jul 01, 2023 Last updated: Jul 01, 2023	Publications: PubMed (1) PubMed: 11967536 Comment: Data included in classification: Deletion resulting in frameshift (PVS1_vstr) The CHEK2 Breast Cancer Consortium (https://doi.org/10.1038/ng879). 1.1% in healthy individuals/5.1% of individuals with breast cancer from … (more) Data included in classification: Deletion resulting in frameshift (PVS1_vstr) The CHEK2 Breast Cancer Consortium (https://doi.org/10.1038/ng879). 1.1% in healthy individuals/5.1% of individuals with breast cancer from 718 families that do not carry mutations in BRCA1 or BRCA2 (P = 0.00000003) (PS4_str) Data not included in classification: Weischer et al 2008 (https://doi.org/10.1200/jco.2007.12.5922) OR 4.8 (95% CI, 3.3 to 7.2) for familial breast cancer, OR is above 2 with lower CI ≥1.5. Wu et al., 2001 (PMID: 11053450), assay reports loss of kinase activity in functional studies. (less) Observation 1: Comment on evidence: 1.1% in healthy individuals/5.1% of individuals with breast cancer from 718 families that do not carry mutations in BRCA1 or BRCA2 (P = 0.00000003) Data … (more) 1.1% in healthy individuals/5.1% of individuals with breast cancer from 718 families that do not carry mutations in BRCA1 or BRCA2 (P = 0.00000003) Data from PMID:11967536 (less) Observation 2: Comment on evidence: Odds Ratio (OR) = 4.8 (95% CI, 3.3 to 7.2) for familial breast cancer. Data from PMID:18172190
Pathogenic (Nov 03, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV002009513.3 First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023
Pathogenic (Aug 23, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000603087.10 First in ClinVar: Sep 30, 2017 Last updated: Feb 20, 2024	Comment: The CHEK2 c.1100delC; p.Thr367MetfsTer15 variant (rs555607708) is a well-studied variant that was originally associated with Li-Fraumeni syndrome (Bell 1999) and has since been reported as … (more) The CHEK2 c.1100delC; p.Thr367MetfsTer15 variant (rs555607708) is a well-studied variant that was originally associated with Li-Fraumeni syndrome (Bell 1999) and has since been reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 128042). This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Additionally, in vitro functional analyses demonstrate a loss of CHEK2 kinase activity, supportive of a pathogenic effect (Lee 2001). This variant is also described as a founder variant in Northern European populations (Cybulski 2004), and is found in the Finnish European population with an allele frequency of 0.87% (219/25124 alleles) in the Genome Aggregation Database. This reduced penetrance variant is associated with an increased breast cancer risk (Bak 2014, Cybulski 2004, Cybulski 2007), and the overall lifetime breast cancer risk for CHEK2 pathogenic variants in general is 20-30% (Slavin 2015). This variant has also been associated with an increased risk of prostate cancer (Naslund-Koch 2016, Pritchard 2016, Wu 2018). There may be additional cancer risks associated with this variant but evidence is incomplete at this time. Based on available information, the c.1100delC variant is considered to be pathogenic. REFERENCES Bak A et al. A risk of breast cancer in women - carriers of constitutional CHEK2 gene mutations, originating from the North - Central Poland. Hered Cancer Clin Pract. 2014 12(1): 10. Bell DW et al. Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science. 1999 286(5449):2528-31. Cybulski C et al. CHEK2 is a multiorgan cancer susceptibility gene. Am J Hum Genet. 2004 75(6):1131-5. Cybulski C et al. A deletion in CHEK2 of 5,395 bp predisposes to breast cancer in Poland. Breast Cancer Res Treat. 2007 102(1):119-22. Lee SB et al. Destabilization of CHK2 by a missense mutation associated with Li-Fraumeni Syndrome. Cancer Res. 2001 61(22):8062-7. Naslund-Koch C et al. Increased Risk for Other Cancers in Addition to Breast Cancer for CHEK2*1100delC Heterozygotes Estimated From the Copenhagen General Population Study. J Clin Oncol. 2016 Apr 10;34(11):1208-16. Pritchard CC et al. Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. N Engl J Med. 2016 Aug 4;375(5):443-53. Slavin TP et al. Clinical Application of Multigene Panels: Challenges of Next-Generation Counseling and Cancer Risk Management. Front Oncol. 2015 5:208. Wu Y et al. A comprehensive evaluation of CHEK2 germline mutations in men with prostate cancer. Prostate. 2018 Jun;78(8):607-615. (less)
Pathogenic (Mar 30, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Baylor Genetics Study: CSER-TexasKidsCanSeq Accession: SCV001481483.3 First in ClinVar: Feb 27, 2021 Last updated: Jun 17, 2024
Pathogenic (Jul 31, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV002552006.5 First in ClinVar: Jul 23, 2022 Last updated: Aug 04, 2024
Pathogenic (May 05, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005197499.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (Nov 20, 2015)	criteria provided, single submitter (Shirts et al. (Genet Med 2016)) Method: clinical testing	Breast and colorectal cancer, susceptibility to Affected status: no, yes Allele origin: germline	University of Washington Department of Laboratory Medicine, University of Washington Accession: SCV000266067.1 First in ClinVar: Mar 20, 2016 Last updated: Mar 20, 2016	Observation 1: Number of individuals with the variant: 1 Clinical Features: breast cancer (present) Age: 40-49 years Observation 2: Number of individuals with the variant: 1 Clinical Features: breast cancer (present) Age: 30-39 years Observation 3: Number of individuals with the variant: 1 Clinical Features: breast cancer (present) Age: 50-59 years Observation 4: Number of individuals with the variant: 1 Clinical Features: phyllodes breast cancer (present) Age: 50-59 years Observation 5: Number of individuals with the variant: 1 Observation 6: Number of individuals with the variant: 1 Observation 7: Number of individuals with the variant: 1 Clinical Features: colon cancer (present) Age: 50-59 years
Pathogenic (-)	criteria provided, single submitter (Silva et al. (BMC Med Genet. 2014)) Method: research	Breast Cancer Affected status: yes Allele origin: germline	A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center Accession: SCV000492465.1 First in ClinVar: Jan 09, 2017 Last updated: Jan 09, 2017	Publications: PubMed (2) PubMed: 23469205‚ 24884479
Pathogenic (May 18, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Familial prostate cancer Bone osteosarcoma Li-Fraumeni syndrome 2 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000611258.1 First in ClinVar: Nov 11, 2017 Last updated: Nov 11, 2017
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Colitis Hematochezia Inflammation of the large intestine Thrombocytopenia Affected status: yes Allele origin: germline	Center for Personalized Medicine, Children's Hospital Los Angeles Accession: SCV000854533.1 First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018	Sex: male
Pathogenic (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	CHEK2-Related Cancer Susceptibility Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000915968.1 First in ClinVar: May 27, 2019 Last updated: May 27, 2019	Publications: PubMed (9) PubMed: 22811390‚ 10617473‚ 11719428‚ 15122511‚ 15492928‚ 16492927‚ 16880452‚ 22006311‚ 21956126 Comment: The CHEK2 c.1100delC (p.Thr367MetfsTer15) variant is a common variant in individuals of European origin and has been investigated in multiple studies in various cancer types. … (more) The CHEK2 c.1100delC (p.Thr367MetfsTer15) variant is a common variant in individuals of European origin and has been investigated in multiple studies in various cancer types. A meta-analysis of ten case-control studies, including 10,860 breast cancer cases and 9,065 controls by the CHEK2 Breast Cancer Case-Control Consortium (2004) found a statistically significant association between carrying the p.Thr367MetfsTer15 variant and increase in risk of breast cancer (OR=2.34). The association of the p.Thr367MetfsTer15 variant and increased risk of breast cancer was also supported by Bernstein et al. (2006) (OR=6.65) and Weischer et al. (2007) (OR=3.2). Weischer et al. (2007) also found an association between the variant and increased risk of prostate cancer (OR=2.3) and colorectal cancer (OR=1.6). Weischer et al. (2012) found an association of the p.Thr367MetfsTer15 variant and increased risk of malignant melanoma in both a case-control study (OR=1.79) and a meta-analysis (OR=1.81). The p.Thr367MetfsTer15 variant has also been identified in patients with Li-Fraumeni syndrome (Bell et al. 1999), colon, kidney, prostate, and thyroid cancers (Cybulski et al. 2004), ovarian cancer (Walsh et al. 2011), and uterine cancer (Pennington et al. 2013), though the associated risks for these cancers due to this variant are unclear at this time. Studies by Lee et al. (2001) found a lack of kinase activity and evidence of loss of heterozygosity in a tumor sample from a patient carrying the germline p.Thr367MetfsTer15 variant. The highest allele frequency reported in the 1000 Genomes database is 0.0202 in the Finnish population. Although an association with the p.Thr367MetfsTer15 variant and susceptibility to different cancers is widely reported, the increase in risk is low to moderate. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
Pathogenic (Apr 19, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary breast ovarian cancer syndrome Affected status: yes Allele origin: germline	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State Accession: SCV002505157.1 First in ClinVar: Apr 30, 2022 Last updated: Apr 30, 2022	Number of individuals with the variant: 1 Geographic origin: South Africa
Pathogenic (Jul 01, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Colorectal cancer Affected status: yes Allele origin: germline	Human Genetics Bochum, Ruhr University Bochum Accession: SCV002758585.1 First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022	Comment: ACMG criteria used to clasify this variant: PVS1, PS3, PS4
Pathogenic (Dec 13, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast (Autosomal dominant inheritance) Affected status: no Allele origin: germline	Genetics and Molecular Pathology, SA Pathology Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002761797.1 First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022
Pathogenic (Jan 20, 2016)	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015)) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000488123.2 First in ClinVar: Jul 01, 2016 Last updated: Dec 24, 2022	Publications: PubMed (9) PubMed: 15492928‚ 19338683‚ 17085682‚ 12533788‚ 15122511‚ 18172190‚ 21807500‚ 22058428‚ 22994785
Pathogenic (Dec 09, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Familial cancer of breast Affected status: no Allele origin: germline	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001368134.4 First in ClinVar: Jul 04, 2020 Last updated: Feb 25, 2023	Comment: PVS1, PS3, PS4_STR, BS1
Pathogenic (Oct 29, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV003806873.1 First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023	Comment: ACMG classification criteria: PVS1 very strong, PS3 supporting, PS4 strong Number of individuals with the variant: 1 Geographic origin: Brazil Method: Paired-end whole-genome sequencing
Pathogenic (Mar 09, 2023)	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023)) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV004020171.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023	Comment: This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	Colorectal cancer (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute of Human Genetics, University Hospital of Duesseldorf Accession: SCV004171175.1 First in ClinVar: Dec 02, 2023 Last updated: Dec 02, 2023
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Hereditary cancer-predisposing syndrome (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Hauer Lab, Department Of Pediatric Oncology, Technical University Munich Accession: SCV004174265.1 First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023	Publications: PubMed (1) PubMed: 37149759 Comment: ACMG/AMP, PVS1, PM2, PP5 Number of individuals with the variant: 1 Clinical Features: tumor (present) Age: 0-19 years
Pathogenic (Jul 21, 2020)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV000601142.5 First in ClinVar: Sep 28, 2017 Last updated: Jan 06, 2024	Publications: PubMed (35) PubMed: 31300551‚ 15087378‚ 27433846‚ 27751358‚ 29489754‚ 29351919‚ 28802053‚ 28874143‚ 28779002‚ 28734145‚ 28727877‚ 28514723‚ 28503720‚ 28195393‚ 28135145‚ 27798748‚ 32119081‚ 32531112‚ 32285038‚ 32383162‚ 31993860‚ 26976419‚ 29522266‚ 10617473‚ 11719428‚ 27269948‚ 27223485‚ 26884562‚ 11967536‚ 15122511‚ 21779515‚ 25431674‚ 15095295‚ 18759107‚ 19768534 Comment: The CHEK2 c.1100del (p.Thr367Metfs15) variant (also known as c.1100delC) alters the translational reading frame of the CHEK2 mRNA and causes the premature termination of CHEK2 … (more) The CHEK2 c.1100del (p.Thr367Metfs15) variant (also known as c.1100delC) alters the translational reading frame of the CHEK2 mRNA and causes the premature termination of CHEK2 protein synthesis. In the published literature, this variant has been reported in individuals with breast cancer and other cancers (PMIDs: 31993860 (2020), 29522266 (2018), 28874143 (2017), 28779002 (2017), 26884562 (2016), 27223485 (2016), 15122511 (2004), 15087378 (2004), 11719428 (2001)). Based on the available information, this variant is classified as pathogenic. (less)
Pathogenic (Apr 24, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Li-Fraumeni syndrome 2 Affected status: yes Allele origin: germline	Institute of Immunology and Genetics Kaiserslautern Accession: SCV005043003.1 First in ClinVar: May 12, 2024 Last updated: May 12, 2024	Comment: ACMG Criteria: PVS1, PS3, PS4, PP4, PP5 Variant was found in heterozygous state Clinical Features: Colon cancer (present)
Pathogenic (Apr 25, 2024)	criteria provided, single submitter (ACGS Best Practice Guidelines for Variant Classification in Rare Disease 2020) Method: clinical testing	Inherited breast cancer and ovarian cancer Affected status: yes Allele origin: germline	Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service Additional submitter: Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service Accession: SCV005061419.1 First in ClinVar: Jun 23, 2024 Last updated: Jun 23, 2024	Comment: PVS1,PS4
Pathogenic (Aug 09, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Li-Fraumeni syndrome 2 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Department of Human Genetics, Hannover Medical School Accession: SCV005186168.1 First in ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024	Clinical Features: Breast carcinoma (present)
Pathogenic (Jun 14, 2024)	criteria provided, single submitter (ACGS Best Practice Guidelines for Variant Classification in Rare Disease 2020) Method: clinical testing	Inherited breast cancer and ovarian cancer Affected status: yes Allele origin: germline	Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service Accession: SCV005196372.1 First in ClinVar: Aug 18, 2024 Last updated: Aug 18, 2024	Comment: PVS1,PS4
Pathogenic (Aug 12, 2024)	criteria provided, single submitter (ACGS Best Practice Guidelines for Variant Classification in Rare Disease 2020) Method: clinical testing	NICE approved PARP inhibitor treatment Affected status: yes Allele origin: germline	Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service Accession: SCV005196385.1 First in ClinVar: Aug 18, 2024 Last updated: Aug 18, 2024	Comment: PVS1,PS4
Pathogenic (Jul 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001245712.24 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Comment: CHEK2: PVS1, PP1:Strong, PS4:Moderate Number of individuals with the variant: 87
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Malignant tumor of breast Affected status: yes Allele origin: unknown	Department of Pathology and Laboratory Medicine, Sinai Health System Additional submitter: Franklin by Genoox Study: The Canadian Open Genetics Repository (COGR) Accession: SCV001549046.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021	Comment: The CHEK2 p.Thr367Metfs15 variant was identified in 1290 of 102960 proband chromosomes (frequency: 0.013) from individuals or families with breast, prostate, and colorectal cancer and … (more) The CHEK2 p.Thr367Metfs15 variant was identified in 1290 of 102960 proband chromosomes (frequency: 0.013) from individuals or families with breast, prostate, and colorectal cancer and was present in 1222 of 292928 control chromosomes (frequency: 0.004) from healthy individuals (Adank 2011, Cybulski 2004, Cybulski 2006, Dong 2003, Easton 2004, Ruijs 2009, Silva 2014, Weischer 2008, Xiang 2011, Yang 2012). The variant was also identified in the following databases: dbSNP (ID: rs555607708) as "With Pathogenic allele", ClinVar (12x, pathogenic), Clinvitae (6x, pathogenic), Cosmic (1x, salivary gland tumour sample), and the Zhejiang Colon Cancer Database (48x). The variant was not identified in the MutDB database. The variant was identified in control databases in 585 of 275092 chromosomes at a frequency of 0.002 (Genome Aggregation Consortium Feb 27, 2017). Of note, it was identified in the Finnish population in 221 of 25794 chromosomes (freq. 0.009) and in the European population in 319 of 125272 chromosomes (freq. 0.003). The c.1100delC variant is an established breast cancer susceptibility allele and is associated with a two- to three-fold increased risk for breast cancer at a median age of 53 years (Naslund-Koch 2016). This variant is also associated with an increased risk of additional cancer types, including prostate, colon, and others (Cybulski 2004, Xiang 2011). Functional studies involving wild-type and mutant CHEK2 proteins expressed in insect cells showed that the p.Thr367Metfs*15 protein lacks kinase activity, supportive of a pathogenic effect (Wu 2001). The c.1100delC variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 367 and leads to a premature stop codon 15 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the CHEK2 gene are an established mechanism of disease and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001932166.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001974642.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
Pathogenic (Sep 27, 2021)	no assertion criteria provided Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. Accession: SCV001977065.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021
Pathogenic (Jul 24, 2014)	no assertion criteria provided Method: clinical testing	Breast carcinoma Affected status: unknown Allele origin: germline	Pathway Genomics Accession: SCV000189922.1 First in ClinVar: Oct 19, 2014 Last updated: Oct 19, 2014
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Leiomyosarcoma Breast neoplasm (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Genome Sciences Centre, British Columbia Cancer Agency Accession: SCV000574565.1 First in ClinVar: May 12, 2017 Last updated: May 12, 2017	Publications: PubMed (1) PubMed: 28514723 Comment: Positive family history of early breast cancer (niece diagnosed at age 35). Whole genome sequencing (blood and tumor) and whole transcriptome sequencing (tumor) also revealed … (more) Positive family history of early breast cancer (niece diagnosed at age 35). Whole genome sequencing (blood and tumor) and whole transcriptome sequencing (tumor) also revealed the germline CHEK2:c.1100delC pathogenic variant, which is considered a moderate penetrance allele for breast cancer. (less) Age: 50-59 years Sex: female
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Study: VKGL Data-share Consensus Accession: SCV001798054.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV001806916.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001743466.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001906450.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Pathogenic (Nov 01, 2006)	no assertion criteria provided Method: literature only	TUMOR PREDISPOSITION SYNDROME 4, BREAST/PROSTATE/COLORECTAL Affected status: not provided Allele origin: germline	OMIM Accession: SCV000026114.4 First in ClinVar: Apr 04, 2013 Last updated: Feb 07, 2021	Publications: PubMed (12) PubMed: 10617473‚ 11479205‚ 11967536‚ 12094328‚ 12533788‚ 12690581‚ 15122511‚ 15466005‚ 16257342‚ 17085682‚ 27711073‚ 36222830 Comment on evidence: In a family with tumor predisposition syndrome-4 (TPDS4; 609265), originally diagnosed with Li-Fraumeni syndrome, Bell et al. (1999) identified deletion of a cytosine at nucleotide … (more) In a family with tumor predisposition syndrome-4 (TPDS4; 609265), originally diagnosed with Li-Fraumeni syndrome, Bell et al. (1999) identified deletion of a cytosine at nucleotide 1100 of the CHK2 gene, resulting in premature termination in the kinase domain of the CHK2 protein. This heterozygous germline mutation was present in all 3 affected family members but was absent from unaffected family members and from 100 control alleles. Affected individuals had classic Li-Fraumeni syndrome with death from breast cancer, glioma, histiocytoma, and sarcoma. Family members had wildtype p53 (191170). Vahteristo et al. (2001) identified the 1100delC mutation in the CHK2 gene in 2 families thought to have an atypical form of Li-Fraumeni syndrome because of the lack of sarcomas and childhood cancers in affected individuals. Meijers-Heijboer et al. (2002) found that an 1100delC variant of CHEK2, which results in truncation of the kinase activity, results in an approximately 2-fold increase of breast cancer risk in women and a 10-fold increase of risk in men. In Finland, Vahteristo et al. (2002) found that the frequency of 1100delC was 2.0% among an unselected population-based cohort of 1,035 patients with breast cancer, as compared with the 1.4% frequency found among 1,885 population control subjects (P = 0.182). However, a 3.1% frequency was found among those 358 patients with a positive family history, giving P = 0.021 compared with population controls. Furthermore, patients with bilateral breast cancer were 6-fold more likely to be 1100delC carriers than were patients with unilateral cancer (P = 0.007). Analysis of the 1100delC variant in an independent set of 507 patients with familial breast cancer with no BRCA1 (113705) or BRCA2 (600185) mutations confirmed a significantly elevated frequency of the 1-bp deletion. Tissue microarray analysis indicated that breast tumors from patients with 1100delC mutations showed reduced CHEK2 immunostaining. The results indicated that CHEK2 acts as a low-penetrance tumor-suppressor gene in breast cancer and that it makes a significant contribution to familial clustering of breast cancer, including families with only 2 affected relatives, which are more common than families that include larger numbers of affected women. Dong et al. (2003) found this frameshift mutation in exon 10 in 1 of 298 men with familial prostate cancer, 1 of 400 men with sporadic prostate cancer, and 4 of 178 prostate cancer tumor samples. The mutation was not found in 423 unaffected men. Meijers-Heijboer et al. (2003) defined a subset of families with hereditary breast cancer characterized by the presence of colorectal cancer (see 114500) cases, which the authors called HBCC. The 1100delC variant was present in 18% of 55 families with HBCC, as compared with 4% of 380 families with breast cancer and without colorectal cancer. The 1100delC mutation was not, however, the major predisposing factor for the HBCC phenotype, but appeared to act in synergy with at least 1 unknown susceptibility gene. To evaluate the breast cancer risk associated with the 1100delC variant, the CHEK2 Breast Cancer Case-Control Consortium (2004) genotyped 10,860 breast cancer cases and 9,065 controls from 10 case-control studies in 5 countries. The 1100delC variant was found in 201 cases (1.9%) and in 64 controls (0.7%), giving an estimated odds ratio of 2.34. There was some evidence of a higher prevalence of the 1100delC variant among cases with a first-degree relative affected with breast cancer (odds ratio 1.44) and of a trend for a higher breast cancer odds ratio at younger ages at diagnosis. These results confirmed that the 1100delC variant confers an increased risk of breast cancer and that this risk is apparent in women unselected for family history. The results were consistent with the hypothesis that the 1100delC variant multiples the risks associated with susceptibility alleles in other genes to increase the risk of breast cancer. Comparing data for 34 breast cancer patients with a germline 1100delC mutation with those for 102 breast cancer patients without this mutation, de Bock et al. (2004) concluded that carrying the 1100delC mutation is an adverse prognostic indicator. Mutation carriers more frequently had a female first- or second-degree relative with breast cancer and had a more unfavorable prognosis regarding the occurrence of contralateral breast cancer and distant metastasis-free survival. Johnson et al. (2005) found that relatives of bilateral breast cancer cases who were wildtype for CHEK2 had 3 times the population risk of female breast cancer, twice the risk of prostate cancer, and a large excess of male breast cancer. Relatives of those who were carriers of CHEK21100delC had an even higher risk of breast cancer and prostate cancer. The results were interpreted as indicating a multiplicative interaction between CHEK21100delC and other unknown susceptibility genes. They suggested that bilateral breast cancer cases and their families are likely to provide an efficient basis for identification of additional low-penetrance breast cancer genes. Cybulski et al. (2006) identified the 1100delC mutation in 14 (0.8%) of 1,864 Polish men with prostate cancer, in 3 (1.2%) of 249 Polish men with familial prostate cancer, and in 12 (0.2%) of 5,496 healthy controls. Data analysis yielded an odds ratio of 5.6 for familial prostate cancer in carriers of the 1-bp deletion. The authors determined that it is a founder mutation. Muranen et al. (2017) genotyped 39,139 breast cancer patients (of whom 624 were 1100delC carriers) and 40,063 healthy controls (of whom 224 were 1100delC carriers) from 32 Breast Cancer Association Consortium studies and analyzed the combined risk effects of CHEK2-1100delC and 77 common variants as a polygenic risk score (PRS) and pairwise interactions. The PRS conferred odds ratios of 1.59 (95% CI, 1.21-2.09) per standard deviation for breast cancer for CHEK2-1100delC carriers and 1.58 (1.55-1.62) for noncarriers. There was no evidence of deviation for the multiplicative model. The OR for the highest quintile was 2.03 (0.86-4.78), placing them in the high-risk category, and the lowest quintile was 0.52 (0.16-1.74), indicating a lifetime risk at the population average. Breen et al. (2022) found that heterozygotes for the c.1100delC variant had an individual risk of colorectal cancer of 0.39% by age 40 to 45 years and thus recommended decreasing their age to initiate routine colonoscopy to age 40. (less)
Pathogenic (Sep 27, 2024)	no assertion criteria provided Method: clinical testing	CHEK2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000806862.4 First in ClinVar: Sep 13, 2018 Last updated: Oct 08, 2024	Comment: The CHEK2 c.1100delC variant is predicted to result in a frameshift and premature protein termination (p.Thr367Metfs15). This variant has been reported to be causative for … (more) The CHEK2 c.1100delC variant is predicted to result in a frameshift and premature protein termination (p.Thr367Metfs15). This variant has been reported to be causative for hereditary breast cancer and uterine serous carcinoma (Bell et al. 1999. PubMed ID: 10617473; Pennington et al. 2013. PubMed ID: 22811390). In a large Danish study, this variant was associated with a statistically-significant increased risk of breast cancer (hazard ratio [HR]: 2.08, 95% CI: 1.51-2.85) and stomach cancer (HR: 5.76, 95%CI: 2.12-15.6; Näslund-Koch et al. 2016. PubMed ID: 26884562). In another study consisting of more than 80,000 breast cancer patients and age-appropriate controls, this variant was reported to have a higher risk for estrogen receptor-positive breast cancer (Schmidt et al. 2016. PubMed ID: 27269948). In addition, this variant has been associated with prostate (Hale et al. 2014. PubMed ID: 25431674) and colorectal cancers (Wasielewski et al. 2008. PubMed ID: 18676774; Xiang et al. 2011. PubMed ID: 21807500). Functional studies have shown that the c.1100del variant impairs CHEK2 activity (Lee et al. 2001. PubMed ID: 11719428; Roeb et al. 2012. PubMed ID: 22419737). This variant is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/128042/). Loss-of-function variants in CHEK2 are known to be pathogenic. This variant is interpreted as pathogenic. (less)
Pathogenic (Nov 14, 2017)	no assertion criteria provided Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	True Health Diagnostics Accession: SCV000787999.1 First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017
Pathogenic (Jun 11, 2019)	no assertion criteria provided Method: clinical testing	Breast and/or ovarian cancer Affected status: yes Allele origin: germline	CZECANCA consortium Accession: SCV001451737.1 First in ClinVar: Dec 24, 2020 Last updated: Dec 24, 2020	Publications: PubMed (1) PubMed: 32295079 Number of individuals with the variant: 2 Ethnicity/Population group: Slavic Geographic origin: Czech Republic
Pathogenic (Mar 04, 2021)	no assertion criteria provided Method: case-control	Carcinoma of pancreas Affected status: yes Allele origin: germline	CZECANCA consortium Accession: SCV001593124.1 First in ClinVar: May 14, 2021 Last updated: May 14, 2021	Number of individuals with the variant: 2 Ethnicity/Population group: Slavic Geographic origin: Czech Republic
Pathogenic (Aug 19, 2021)	no assertion criteria provided Method: clinical testing	Breast carcinoma Affected status: yes Allele origin: germline	Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences Accession: SCV001792259.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021	Comment: Invasive Ductal Carcinoma Estrogen Receptor: Positive Progesterone Receptor: Positive HER2 Receptor: Positive Age: 30-39 years
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001954678.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Pathogenic (Jul 26, 2021)	no assertion criteria provided Method: clinical testing	Bone osteosarcoma Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein Accession: SCV002011794.1 First in ClinVar: Nov 06, 2021 Last updated: Nov 06, 2021
Pathogenic (Aug 26, 2022)	no assertion criteria provided Method: clinical testing	Familial cancer of breast Affected status: yes Allele origin: germline	BRCAlab, Lund University Accession: SCV002588975.1 First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023
Pathogenic (Nov 22, 2021)	no assertion criteria provided Method: clinical testing	Breast cancer, susceptibility to Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV002070848.3 First in ClinVar: Jan 29, 2022 Last updated: Dec 11, 2022	Comment: DNA sequence analysis of the CHEK2 gene demonstrated a single base pair deletion in exon 11, c.1100del. This pathogenic sequence change results in an amino … (more) DNA sequence analysis of the CHEK2 gene demonstrated a single base pair deletion in exon 11, c.1100del. This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon 15 amino acids downstream of the sequence change, p.Thr367Metfs*15. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated CHEK2 protein with potentially abnormal function. In vitro functional studies have demonstrated that CHEK2 c.1100del change results in loss of kinase activity and the inability to phosphorylate Cdc25C, supportive of a pathogenic effect (PMIDs: 11719428, 11053450). This pathogenic sequence change is a well-known founder pathogenic variant with relative frequency in European populations. It is associated with an increased risk for cancer and has been described in multiple patients with CHEK2-related cancers, including breast cancer, lung cancer, thyroid cancer, gastric cancer, renal cancer, lymphoma and in individuals with possible Li-Fraumeni syndrome (PMID: 21956126, 23296741, 26884562, PMID: 26506619). (less)
Pathogenic (Nov 24, 2023)	no assertion criteria provided Method: clinical testing	Li-Fraumeni syndrome 2 Affected status: yes Allele origin: germline	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas Accession: SCV004171570.1 First in ClinVar: Dec 02, 2023 Last updated: Dec 02, 2023
Pathogenic (Jul 28, 2023)	no assertion criteria provided Method: clinical testing	Ovarian cancer Affected status: yes Allele origin: germline	Diagnostics Centre, Carl Von Ossietzky University Oldenburg Accession: SCV004174182.1 First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023	Publications: PubMed (6) PubMed: 16492927‚ 23109706‚ 21956126‚ 16880452‚ 28727877‚ 37055167 Comment: The variant CHEK2:c.1100delC, p.(Thr367fs), which is located in the coding exon 11 of the CHEK2 gene, results from a deletion of a nucleotide at position … (more) The variant CHEK2:c.1100delC, p.(Thr367fs), which is located in the coding exon 11 of the CHEK2 gene, results from a deletion of a nucleotide at position 1100. The variant causes a frameshift that results on the replace of threonine residue at protein position 367 by methionine and a premature stop codon follows after further 15 amino acids. The premature stop codon is predicted to cause protein truncation/absent and nonsense mediated decay in a gene where loss-of-function is a mechanism of disease. Multiple studies has shown that the variant is statistically significant associated to increased risk of breast and other type of cancer, including ovarian cancer (PMID: 16492927; 23109706; 21956126; 16880452; 28727877; 37055167). In one study, tumours were also detected statistically significantly more frequently in mice with the CHEK2 c.1100delC variant as compared to wild-type controls (PMID: 19805189). This variant is a known founder variant in the overall population and occurs with an allele frequency of < 1 % in gnomAD. The variant is classified as Pathogenic. (less) Number of individuals with the variant: 1 Age: 50-59 years Sex: female
not provided (-)	no classification provided Method: phenotyping only	Not Provided Affected status: yes, unknown Allele origin: unknown	GenomeConnect, ClinGen Accession: SCV000607207.2 First in ClinVar: Oct 16, 2017 Last updated: Jul 19, 2020	Comment: Variant interpretted as Pathogenic and reported most recently on 12-09-2019 by Lab or GTR ID 505849. The variant was also interpretted as pathogenic ad reported … (more) Variant interpretted as Pathogenic and reported most recently on 12-09-2019 by Lab or GTR ID 505849. The variant was also interpretted as pathogenic ad reported on 03-04-2017 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less) Observation 1: Number of individuals with the variant: 1 Clinical Features: Myopia (disease) (present) , Seizures (present) , Bleeding with minor or no trauma (present) , Epistaxis (present) , Abnormality of leukocytes (present) , Bruising susceptibility … (more) Myopia (disease) (present) , Seizures (present) , Bleeding with minor or no trauma (present) , Epistaxis (present) , Abnormality of leukocytes (present) , Bruising susceptibility (present) , Breast carcinoma (present) , Abnormality of blood and blood-forming tissues (present) (less) Indication for testing: Diagnostic Age: 50-59 years Sex: female Method: Sanger Sequencing Testing laboratory: GeneDx Date variant was reported to submitter: 2017-03-04 Testing laboratory interpretation: Pathogenic Observation 2: Number of individuals with the variant: 1 Clinical Features: Myopia (disease) (present) Age: 40-49 years Sex: female Method: Sanger Sequencing Testing laboratory: Color Health, Inc Date variant was reported to submitter: 2016-10-11 Testing laboratory interpretation: Pathogenic Observation 3: Number of individuals with the variant: 1 Clinical Features: Hyperthyroidism (present) , Abnormality of the hair (present) , Tinnitus (present) , Hyperacusis (present) , Vertigo (present) , Abnormality of coordination (present) , Memory impairment … (more) Hyperthyroidism (present) , Abnormality of the hair (present) , Tinnitus (present) , Hyperacusis (present) , Vertigo (present) , Abnormality of coordination (present) , Memory impairment (present) , Anxiety (present) , Depressivity (present) , Delusions (present) , Hallucinations (present) , Obsessive-compulsive behavior (present) , Short attention span (present) , Atrophic scars (present) , Hyperpigmentation of the skin (present) , Hypopigmentation of the skin (present) , Cutaneous photosensitivity (present) , Thickened skin (present) , Abnormality of the curvature of the vertebral column (present) , Abnormality of the foot (present) , Abnormality of muscle physiology (present) , Arrhythmia (present) , Abnormal EKG (present) , Abnormal pattern of respiration (present) , Abnormality of the stomach (present) , Abnormality of the liver (present) , Abnormality of the intestine (present) , Abnormality of the large intestine (present) , Abnormality of urine homeostasis (present) , Persistent bleeding after trauma (present) , Abnormality of thrombocytes (present) , Abnormality of erythrocytes (present) , Periodontitis (present) (less) Age: 40-49 years Sex: female Testing laboratory: Color Health, Inc Date variant was reported to submitter: 2019-12-09 Testing laboratory interpretation: Pathogenic
not provided (-)	no classification provided Method: phenotyping only	CHEK2-related cancer predisposition Affected status: yes, unknown Allele origin: unknown	GenomeConnect - Invitae Patient Insights Network Accession: SCV001749628.1 First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021	Comment: Variant reported in multiple Invitae PIN participants by multiple clinical testing laboratories. Variant interpreted as Pathogenic by all laboratories and reported most recently on 9/2/2020 … (more) Variant reported in multiple Invitae PIN participants by multiple clinical testing laboratories. Variant interpreted as Pathogenic by all laboratories and reported most recently on 9/2/2020 by Invitae, 2/22/2016 by Ambry Genetics, 12/16/2016 by Myriad, 3/4/2017 by GeneDx, and 9/11/17 by Myriad Women's Health. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less) Observation 1: Number of individuals with the variant: 1 Clinical Features: Family history (present) Indication for testing: Presymptomatic\|Family Testing Age: 60-69 years Sex: male Testing laboratory: Invitae Date variant was reported to submitter: 2017-12-20 Testing laboratory interpretation: Pathogenic Observation 2: Number of individuals with the variant: 1 Clinical Features: Family history of cancer (present) , Intestinal polyp (present) Age: 40-49 years Sex: female Testing laboratory: Myriad Genetic Laboratories, Inc., Myriad Genetic Laboratories, Inc. Date variant was reported to submitter: 2016-12-16 Testing laboratory interpretation: Pathogenic Observation 3: Number of individuals with the variant: 1 Clinical Features: Breast carcinoma (present) , Acute lymphoid leukemia (present) Indication for testing: Diagnostic Age: 50-59 years Sex: female Ethnicity/Population group: Caucasians MedGen:C0043157 Method: Sanger Sequencing Testing laboratory: GeneDx Date variant was reported to submitter: 2017-03-04 Testing laboratory interpretation: Pathogenic Observation 4: Number of individuals with the variant: 1 Clinical Features: Abnormality of vision (present) , Myopia (present) , Abnormal intestine morphology (present) , Hyperthyroidism (present) Indication for testing: Family Testing Age: 60-69 years Sex: male Testing laboratory: Myriad Genetics, Inc. Date variant was reported to submitter: 2017-09-11 Testing laboratory interpretation: Pathogenic Observation 5: Number of individuals with the variant: 1 Clinical Features: Skin basal cell carcinoma (present) Indication for testing: Family Testing Age: 50-59 years Sex: female Ethnicity/Population group: Caucasians MedGen:C0043157 Testing laboratory: Ambry Genetics Date variant was reported to submitter: 2016-02-22 Testing laboratory interpretation: Pathogenic Observation 6: Number of individuals with the variant: 1 Clinical Features: Thyroid gland carcinoma (present) , Non-Hodgkin lymphoma (present) , Family history of cancer (present) Indication for testing: Diagnostic Age: 50-59 years Sex: female Testing laboratory: Invitae Date variant was reported to submitter: 2019-12-27 Testing laboratory interpretation: Pathogenic Observation 7: Number of individuals with the variant: 1 Clinical Features: Breast carcinoma (present) , Family history of cancer (present) Indication for testing: Diagnostic Age: 50-59 years Sex: female Testing laboratory: Invitae Date variant was reported to submitter: 2020-05-27 Testing laboratory interpretation: Pathogenic Observation 8: Number of individuals with the variant: 1 Clinical Features: Abnormal intestine morphology (present) , Abnormal stomach morphology (present) , Hyperthyroidism (present) , Seizure (present) , Pregnancy history (present) , Premature birth (present) Indication for testing: Presymptomatic Age: 50-59 years Sex: female Testing laboratory: Invitae Date variant was reported to submitter: 2020-01-23 Testing laboratory interpretation: Pathogenic Observation 9: Number of individuals with the variant: 1 Clinical Features: Family history of cancer (present) Indication for testing: Presymptomatic\|Family Testing Age: 60-69 years Sex: female Testing laboratory: Invitae Date variant was reported to submitter: 2020-09-02 Testing laboratory interpretation: Pathogenic
Uncertain significance (-)	Flagged submission flagged submission (ACMG Guidelines, 2015) Method: clinical testing Reason: Clinical significance appears to be a case-level interpretation inconsistent with variant classification Source: ClinGen	Astrocytoma Affected status: yes Allele origin: somatic	Laboratory of Molecular Neuropathology, The University of Texas Health Science Center at Houston Accession: SCV000692550.1 First in ClinVar: Apr 02, 2018 Last updated: Apr 02, 2018
click to load more click to collapse
Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more

Comment:

This variant is also referred to as c.1100delC (p.Thr367MetfsTer15) (NM_007194.3) in the literature. This deletion in exon 12 of 16 causes a frameshift and a premature stop codon at residue 424 and is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). The c.1229del (p.Thr410MetfsTer15) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.2% (585/275092) and is present in the homozygous state at a frequency of 0.0004% (1/275092). This variant is enriched in the European (Finnish) population (MAF=0.87%). Based on two large case-control studies, the relative risk for female breast cancer associated with the c.1229del variant was 3.0 (90% CI, 2.6-3.5) (PMID: 26014596, 15122511, 23109706). Additionally, a meta-analysis reported a relative risk of 1.88 (95% C.I. 1.29-2.73) for colorectal cancer associated with the c.1229del variant (PMID: 23946381). The c.1229del variant has also been associated with an increased risk of prostate cancer (PMID: 26629066) and other cancers (PMID: 26884562, 21956126). Based on the available evidence, the c.1229del (p.Thr410MetfsTer15) variant is classified as Pathogenic.

Comment:

This variant deletes 1 nucleotide in exon 11 of the CHEK2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. A large meta-analysis of breast cancer case-control studies has determined that female carriers of this variant show a relative risk for familial breast cancer of 4.8 (95% CI: [3.3, 7.2]) and cumulative risk at age 70 years of 37% (95% CI: [26, 56]) vs. 7.8% for the population controls (PMID: 18172190). Another meta-analysis has also shown a significant breast cancer risk in heterozygous carriers of this variant (OR=2.75, 95% CI: [2.25, 3.36]) (PMID: 22994785). The ORs and CIs were 2.33 (95% CI: [1.79, 3.05]), 3.72 (95% CI: [2.61, 5.31]) and 2.78 (95% CI: [2.28, 3.39]), respectively, in unselected, family, early-onset breast cancer subgroups in this study. This variant has been observed in individuals affected with colorectal cancer, but whether this variant is associated with increased risk of colorectal cancer remains uncertain (PMID: 21807500, 28135145, 28734145). This variant is well documented as a breast cancer-associated variant in the literature and in the public database (ClinVar variation ID: 128042). This variant has been identified in 591/280390 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of CHEK2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Thr367Metfs*15) in the CHEK2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CHEK2 are known to be pathogenic (PMID: 21876083, 24713400). This variant is present in population databases (rs555607708, gnomAD 0.9%), and has an allele count higher than expected for a pathogenic variant. This particular variant has been well described in the literature. In a large meta-analysis comprising 16 studies including 26,488 affected individuals and 27,402 controls, women heterozygous for this variant have a relative risk for familial breast cancer of 4.8 (95% CI, 3.3-7.2). The cumulative risk at age 70 years is 37% (95% CI, 26%-56%), compared to 7.8% for the average Caucasian woman in the general population (PMID: 18172190). Although one study has reported that the c.1100del variant confers an approximate 10-fold increased risk of male breast cancer (PMID: 11967536), the results have yet to be confirmed in further studies (PMID: 14648717, 14648718, 14648719, 15488637). ClinVar contains an entry for this variant (Variation ID: 128042). For these reasons, this variant has been classified as Pathogenic.

Comment:

The c.1100delC (p.T367Mfs*15) alteration, located in exon 11 (coding exon 10) of the CHEK2 gene, consists of a deletion of one nucleotide at position 1100, causing a translational frameshift with a predicted alternate stop codon after 15 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Clinic-based studies have estimated an approximately 2-fold increase in female breast cancer, colorectal cancer, and melanoma risk associated with this alteration (CHEK2 Breast Cancer Case-Control, 2004; Xiang, 2011; Weischer, 2012). However, a recent population-based study found a 2-fold increase in female breast cancer risk and 6-fold increase in stomach cancer risk associated with this alteration, but did not find a statistically significant association with colon cancer or melanoma (Näslund-Koch, 2016). Another study found that risk for estrogen receptor (ER) positive breast cancer was more pronounced than risk for ER-negative breast cancer and estimated that the cumulative risks for development of ER-positive and ER-negative tumors by age 80 in carriers were 20% and 3%, respectively, compared with 9% and 2%, respectively, in the general population of the United Kingdom (Schmidt, 2016). This alteration has also been reported in male breast cancer cohorts (Leedom, 2016; Hallamies, 2017), and was identified in 5/692 men with metastatic prostate cancer who were unselected for family history of cancer or age at diagnosis (Pritchard, 2016). This alteration is located within the kinase domain, and is reported to abolish the kinase activity of CHK2 (Wu, 2001). Based on the available evidence, this alteration is classified as pathogenic.

Comment:

The c.1100delC (p.Thr367fs) variant in CHEK2 has been associated with increased risk for several types of cancer, including breast, colorectal, and prostate. Me ta-analyses have reported an odds ratio of 2-4 for developing breast, colorectal , or prostate cancer, and a possibly smaller increased risk of malignant melanom a (Weischer 2008, Xiang 2011, Weischer 2012, Yang 2012, Wang 2015). In addition, animal models in mice have shown that this variant causes increased tumor forma tion in multiple cancer sites (Bahassi 2009). This variant has also been reporte d by other clinical laboratories in ClinVar (Variation ID 128042). Of note, this variant has been identified in 0.3% (319/125272) of European chromosomes by the genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs 35705950). Therefore, this variant is not expected to cause highly penetrant Men delian disease. In summary, the c.1100delC (p.Thr367fs) variant is an establishe d risk factor for breast, colorectal, and prostate cancers.

Comment:

Variant summary: CHEK2 c.1100delC (p.Thr367MetfsX15) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 0.002 in 248982 control chromosomes (gnomAD). Although this variant was found at a relatively high frequency in controls, this is a well-known founder mutation that is known to be relatively frequent in European populations. c.1100delC has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome and also as risk factor for several cancer types (breast, ovarian, prostate, colon, etc.). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated that this variant leads to loss of damage response and kinase activity (Lee_2001, Roeb_2012). Eighteen other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

This variation is a deletion of 1 nucleotide from exon 11 of the CHEK2 mRNA (c.1100delC), causing a frameshift at codon 367. This creates a premature translational stop signal 15 amino acid residues later (p.Thr367Metfs*15) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in CHEK2 are known to be pathogenic. This variant has been well described in the literature (PMID: 18172190). The mutation database ClinVar contains an entry for this variant (Variation ID: 128042).

Comment:

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect: loss of kinase activity (Lee 2001, Wu 2001); Case control studies suggest this variant is associated with several types of cancer, including breast, colon, prostate, gastric, renal, and thyroid (Seppala 2003, The CHEK2 Breast Cancer Consortium 2004, Cybulski 2006, Desrichard 2011, Teodorczyk 2013, Hale 2014, Ma 2014, Siolek 2015, Naslund-Koch 2016, Schmidt 2016, Couch 2017, Decker 2017, Katona 2017, Carlo 2018); This variant is associated with the following publications: (PMID: 11967536, 14648718, 18759107, 27269948, 14612911, 15122511, 17085682, 22114986, 23296741, 25431674, 23946381, 25583358, 26884562, 28418444, 28779002, 28734145, 29978187, 11719428, 11053450, 31948886, 32832836, 31980526, 32854451, 31263571, 32081490, 31447099, 32255556, 15818573, 32285038, 30777372, 31871297, 30957677, 31206626, 28514723, 31263054, 30877237, 31360903, 30612635, 30303537, 30676620, 30113427, 31159747, 30833417, 31090900, 30309722, 30322717, 29767408, 30623166, 29520813, 29445900, 30947698, 30426508, 29506128, 15095295, 30333958, 28135145, 29909963, 28727877, 25186627, 26556299, 28503720, 28802053, 27806230, 27798748, 28195393, 29489754, 28125075, 19768534, 29351919, 28944238, 29146883, 26332814, 29909568, 28874143, 25980754, 26681312, 22527104, 27083775, 26822237, 27153395, 26084796, 26641009, 27716369, 27488870, 21956126, 27751358, 28008555, 27433846, 27443514, 17661168, 16452051, 15087378, 21807500, 12690581, 14648719, 10617473, 15239132, 22006311, 23409019, 22058428, 23109706, 21876083, 22058216, 20722467, 23415889, 22811390, 19030985, 22520019, 21244692, 22691310, 22994785, 15492928, 23329222, 25835597, 24723567)

Comment:

The CHEK2 c.1100del (p.Thr367MetfsTer15) change causes a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of the protein due to nonsense mediated decay (PVS1). This variant has been widely reported to be associated with cancer susceptibility, including significant associations with increased risk of breast cancer in large meta-analysis studies (odds ratios ~2-5, PMID: 18172190, 22994785). This variant has also been reported in individuals with colon, prostate, gastric, kidney, and thyroid cancer (PMID: 14612911, 15087378, 15492928, 16880452, 21807500, 23296741, 25431674, 25583358, 26884562). This change has an overall frequency of 0.21% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/) and has been described as a founder variant in Northern European populations (PMID: 15087378). In summary, this variant meets criteria to be classified as pathogenic with evidence indicating lower penetrance.

Comment:

Data included in classification: Deletion resulting in frameshift (PVS1_vstr) The CHEK2 Breast Cancer Consortium (https://doi.org/10.1038/ng879). 1.1% in healthy individuals/5.1% of individuals with breast cancer from 718 families that do not carry mutations in BRCA1 or BRCA2 (P = 0.00000003) (PS4_str) Data not included in classification: Weischer et al 2008 (https://doi.org/10.1200/jco.2007.12.5922) OR 4.8 (95% CI, 3.3 to 7.2) for familial breast cancer, OR is above 2 with lower CI ≥1.5. Wu et al., 2001 (PMID: 11053450), assay reports loss of kinase activity in functional studies.

Comment:

The CHEK2 c.1100delC; p.Thr367MetfsTer15 variant (rs555607708) is a well-studied variant that was originally associated with Li-Fraumeni syndrome (Bell 1999) and has since been reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 128042). This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Additionally, in vitro functional analyses demonstrate a loss of CHEK2 kinase activity, supportive of a pathogenic effect (Lee 2001). This variant is also described as a founder variant in Northern European populations (Cybulski 2004), and is found in the Finnish European population with an allele frequency of 0.87% (219/25124 alleles) in the Genome Aggregation Database. This reduced penetrance variant is associated with an increased breast cancer risk (Bak 2014, Cybulski 2004, Cybulski 2007), and the overall lifetime breast cancer risk for CHEK2 pathogenic variants in general is 20-30% (Slavin 2015). This variant has also been associated with an increased risk of prostate cancer (Naslund-Koch 2016, Pritchard 2016, Wu 2018). There may be additional cancer risks associated with this variant but evidence is incomplete at this time. Based on available information, the c.1100delC variant is considered to be pathogenic. REFERENCES Bak A et al. A risk of breast cancer in women - carriers of constitutional CHEK2 gene mutations, originating from the North - Central Poland. Hered Cancer Clin Pract. 2014 12(1): 10. Bell DW et al. Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science. 1999 286(5449):2528-31. Cybulski C et al. CHEK2 is a multiorgan cancer susceptibility gene. Am J Hum Genet. 2004 75(6):1131-5. Cybulski C et al. A deletion in CHEK2 of 5,395 bp predisposes to breast cancer in Poland. Breast Cancer Res Treat. 2007 102(1):119-22. Lee SB et al. Destabilization of CHK2 by a missense mutation associated with Li-Fraumeni Syndrome. Cancer Res. 2001 61(22):8062-7. Naslund-Koch C et al. Increased Risk for Other Cancers in Addition to Breast Cancer for CHEK2*1100delC Heterozygotes Estimated From the Copenhagen General Population Study. J Clin Oncol. 2016 Apr 10;34(11):1208-16. Pritchard CC et al. Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. N Engl J Med. 2016 Aug 4;375(5):443-53. Slavin TP et al. Clinical Application of Multigene Panels: Challenges of Next-Generation Counseling and Cancer Risk Management. Front Oncol. 2015 5:208. Wu Y et al. A comprehensive evaluation of CHEK2 germline mutations in men with prostate cancer. Prostate. 2018 Jun;78(8):607-615.

Comment:

The CHEK2 c.1100delC (p.Thr367MetfsTer15) variant is a common variant in individuals of European origin and has been investigated in multiple studies in various cancer types. A meta-analysis of ten case-control studies, including 10,860 breast cancer cases and 9,065 controls by the CHEK2 Breast Cancer Case-Control Consortium (2004) found a statistically significant association between carrying the p.Thr367MetfsTer15 variant and increase in risk of breast cancer (OR=2.34). The association of the p.Thr367MetfsTer15 variant and increased risk of breast cancer was also supported by Bernstein et al. (2006) (OR=6.65) and Weischer et al. (2007) (OR=3.2). Weischer et al. (2007) also found an association between the variant and increased risk of prostate cancer (OR=2.3) and colorectal cancer (OR=1.6). Weischer et al. (2012) found an association of the p.Thr367MetfsTer15 variant and increased risk of malignant melanoma in both a case-control study (OR=1.79) and a meta-analysis (OR=1.81). The p.Thr367MetfsTer15 variant has also been identified in patients with Li-Fraumeni syndrome (Bell et al. 1999), colon, kidney, prostate, and thyroid cancers (Cybulski et al. 2004), ovarian cancer (Walsh et al. 2011), and uterine cancer (Pennington et al. 2013), though the associated risks for these cancers due to this variant are unclear at this time. Studies by Lee et al. (2001) found a lack of kinase activity and evidence of loss of heterozygosity in a tumor sample from a patient carrying the germline p.Thr367MetfsTer15 variant. The highest allele frequency reported in the 1000 Genomes database is 0.0202 in the Finnish population. Although an association with the p.Thr367MetfsTer15 variant and susceptibility to different cancers is widely reported, the increase in risk is low to moderate. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Comment:

The CHEK2 c.1100del (p.Thr367Metfs*15) variant (also known as c.1100delC) alters the translational reading frame of the CHEK2 mRNA and causes the premature termination of CHEK2 protein synthesis. In the published literature, this variant has been reported in individuals with breast cancer and other cancers (PMIDs: 31993860 (2020), 29522266 (2018), 28874143 (2017), 28779002 (2017), 26884562 (2016), 27223485 (2016), 15122511 (2004), 15087378 (2004), 11719428 (2001)). Based on the available information, this variant is classified as pathogenic.

Comment:

The CHEK2 p.Thr367Metfs*15 variant was identified in 1290 of 102960 proband chromosomes (frequency: 0.013) from individuals or families with breast, prostate, and colorectal cancer and was present in 1222 of 292928 control chromosomes (frequency: 0.004) from healthy individuals (Adank 2011, Cybulski 2004, Cybulski 2006, Dong 2003, Easton 2004, Ruijs 2009, Silva 2014, Weischer 2008, Xiang 2011, Yang 2012). The variant was also identified in the following databases: dbSNP (ID: rs555607708) as "With Pathogenic allele", ClinVar (12x, pathogenic), Clinvitae (6x, pathogenic), Cosmic (1x, salivary gland tumour sample), and the Zhejiang Colon Cancer Database (48x). The variant was not identified in the MutDB database. The variant was identified in control databases in 585 of 275092 chromosomes at a frequency of 0.002 (Genome Aggregation Consortium Feb 27, 2017). Of note, it was identified in the Finnish population in 221 of 25794 chromosomes (freq. 0.009) and in the European population in 319 of 125272 chromosomes (freq. 0.003). The c.1100delC variant is an established breast cancer susceptibility allele and is associated with a two- to three-fold increased risk for breast cancer at a median age of 53 years (Naslund-Koch 2016). This variant is also associated with an increased risk of additional cancer types, including prostate, colon, and others (Cybulski 2004, Xiang 2011). Functional studies involving wild-type and mutant CHEK2 proteins expressed in insect cells showed that the p.Thr367Metfs*15 protein lacks kinase activity, supportive of a pathogenic effect (Wu 2001). The c.1100delC variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 367 and leads to a premature stop codon 15 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the CHEK2 gene are an established mechanism of disease and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic.

Comment:

Positive family history of early breast cancer (niece diagnosed at age 35). Whole genome sequencing (blood and tumor) and whole transcriptome sequencing (tumor) also revealed the germline CHEK2:c.1100delC pathogenic variant, which is considered a moderate penetrance allele for breast cancer.

Comment:

The CHEK2 c.1100delC variant is predicted to result in a frameshift and premature protein termination (p.Thr367Metfs*15). This variant has been reported to be causative for hereditary breast cancer and uterine serous carcinoma (Bell et al. 1999. PubMed ID: 10617473; Pennington et al. 2013. PubMed ID: 22811390). In a large Danish study, this variant was associated with a statistically-significant increased risk of breast cancer (hazard ratio [HR]: 2.08, 95% CI: 1.51-2.85) and stomach cancer (HR: 5.76, 95%CI: 2.12-15.6; Näslund-Koch et al. 2016. PubMed ID: 26884562). In another study consisting of more than 80,000 breast cancer patients and age-appropriate controls, this variant was reported to have a higher risk for estrogen receptor-positive breast cancer (Schmidt et al. 2016. PubMed ID: 27269948). In addition, this variant has been associated with prostate (Hale et al. 2014. PubMed ID: 25431674) and colorectal cancers (Wasielewski et al. 2008. PubMed ID: 18676774; Xiang et al. 2011. PubMed ID: 21807500). Functional studies have shown that the c.1100del variant impairs CHEK2 activity (Lee et al. 2001. PubMed ID: 11719428; Roeb et al. 2012. PubMed ID: 22419737). This variant is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/128042/). Loss-of-function variants in CHEK2 are known to be pathogenic. This variant is interpreted as pathogenic.

Comment:

DNA sequence analysis of the CHEK2 gene demonstrated a single base pair deletion in exon 11, c.1100del. This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon 15 amino acids downstream of the sequence change, p.Thr367Metfs*15. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated CHEK2 protein with potentially abnormal function. In vitro functional studies have demonstrated that CHEK2 c.1100del change results in loss of kinase activity and the inability to phosphorylate Cdc25C, supportive of a pathogenic effect (PMIDs: 11719428, 11053450). This pathogenic sequence change is a well-known founder pathogenic variant with relative frequency in European populations. It is associated with an increased risk for cancer and has been described in multiple patients with CHEK2-related cancers, including breast cancer, lung cancer, thyroid cancer, gastric cancer, renal cancer, lymphoma and in individuals with possible Li-Fraumeni syndrome (PMID: 21956126, 23296741, 26884562, PMID: 26506619).

Comment:

The variant CHEK2:c.1100delC, p.(Thr367fs), which is located in the coding exon 11 of the CHEK2 gene, results from a deletion of a nucleotide at position 1100. The variant causes a frameshift that results on the replace of threonine residue at protein position 367 by methionine and a premature stop codon follows after further 15 amino acids. The premature stop codon is predicted to cause protein truncation/absent and nonsense mediated decay in a gene where loss-of-function is a mechanism of disease. Multiple studies has shown that the variant is statistically significant associated to increased risk of breast and other type of cancer, including ovarian cancer (PMID: 16492927; 23109706; 21956126; 16880452; 28727877; 37055167). In one study, tumours were also detected statistically significantly more frequently in mice with the CHEK2 c.1100delC variant as compared to wild-type controls (PMID: 19805189). This variant is a known founder variant in the overall population and occurs with an allele frequency of < 1 % in gnomAD. The variant is classified as Pathogenic.

Comment:

Variant interpretted as Pathogenic and reported most recently on 12-09-2019 by Lab or GTR ID 505849. The variant was also interpretted as pathogenic ad reported on 03-04-2017 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

Comment:

Variant reported in multiple Invitae PIN participants by multiple clinical testing laboratories. Variant interpreted as Pathogenic by all laboratories and reported most recently on 9/2/2020 by Invitae, 2/22/2016 by Ambry Genetics, 12/16/2016 by Myriad, 3/4/2017 by GeneDx, and 9/11/17 by Myriad Women's Health. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain function			Laboratory of Molecular Neuropathology, The University of Texas Health Science Center at Houston Accession: SCV000692550.1

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
A clinical screening tool to detect genetic cancer predisposition in pediatric oncology shows high sensitivity but can miss a substantial percentage of affected children.	Friedrich UA	Genetics in medicine : official journal of the American College of Medical Genetics	2023	PMID: 37149759
Detection of pathogenic variants in breast cancer susceptibility genes in bilateral breast cancer.	Evans DG	Journal of medical genetics	2023	PMID: 37055167
An updated counseling framework for moderate-penetrance colorectal cancer susceptibility genes.	Breen KE	Genetics in medicine : official journal of the American College of Medical Genetics	2022	PMID: 36222830
Skin cancer risk in CHEK2 mutation carriers.	Bui AN	Journal of the European Academy of Dermatology and Venereology : JEADV	2021	PMID: 32531112
Clustering of known low and moderate risk alleles rather than a novel recessive high-risk gene in non-BRCA1/2 sib trios affected with breast cancer.	Hilbers FS	International journal of cancer	2020	PMID: 32383162
Bilateral Paget's Disease of the Breast in a Patient with CHEK2 Mutation.	Owusu-Brackett N	European journal of breast health	2020	PMID: 32285038
Radiation Treatment, ATM, BRCA1/2, and CHEK2*1100delC Pathogenic Variants and Risk of Contralateral Breast Cancer.	Reiner AS	Journal of the National Cancer Institute	2020	PMID: 32119081
High risk of breast cancer in women with biallelic pathogenic variants in CHEK2.	Rainville I	Breast cancer research and treatment	2020	PMID: 31993860
One in three highly selected Greek patients with breast cancer carries a loss-of-function variant in a cancer susceptibility gene.	Fostira F	Journal of medical genetics	2020	PMID: 31300551
Association Between CHEK2*1100delC and Breast Cancer: A Systematic Review and Meta-Analysis.	Liang M	Molecular diagnosis & therapy	2018	PMID: 29909568
Gene panel testing of 5589 BRCA1/2-negative index patients with breast cancer in a routine diagnostic setting: results of the German Consortium for Hereditary Breast and Ovarian Cancer.	Hauke J	Cancer medicine	2018	PMID: 29522266
The landscape of genomic alterations across childhood cancers.	Gröbner SN	Nature	2018	PMID: 29489754
High Yield of Pathogenic Germline Mutations Causative or Likely Causative of the Cancer Phenotype in Selected Children with Cancer.	Diets IJ	Clinical cancer research : an official journal of the American Association for Cancer Research	2018	PMID: 29351919
Gene-panel testing of breast and ovarian cancer patients identifies a recurrent RAD51C duplication.	Pelttari LM	Clinical genetics	2018	PMID: 28802053
CHEK2 c.1100delC mutation is associated with an increased risk for male breast cancer in Finnish patient population.	Hallamies S	BMC cancer	2017	PMID: 28874143
Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks.	Decker B	Journal of medical genetics	2017	PMID: 28779002
Colorectal cancer risk associated with the CHEK2 1100delC variant.	Katona BW	European journal of cancer (Oxford, England : 1990)	2017	PMID: 28734145
Genetic Predisposition to Breast Cancer Due to Mutations Other Than BRCA1 and BRCA2 Founder Alleles Among Ashkenazi Jewish Women.	Walsh T	JAMA oncology	2017	PMID: 28727877
Genomic profiling of pelvic genital type leiomyosarcoma in a woman with a germline CHEK2:c.1100delC mutation and a concomitant diagnosis of metastatic invasive ductal breast carcinoma.	Thibodeau ML	Cold Spring Harbor molecular case studies	2017	PMID: 28514723
Contribution of germline mutations in cancer predisposition genes to tumor etiology in young women diagnosed with invasive breast cancer.	Rummel SK	Breast cancer research and treatment	2017	PMID: 28503720
Use of multigene-panel identifies pathogenic variants in several CRC-predisposing genes in patients previously tested for Lynch Syndrome.	Hansen MF	Clinical genetics	2017	PMID: 28195393
Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer.	Yurgelun MB	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2017	PMID: 28135145
Revisiting breast cancer patients who previously tested negative for BRCA mutations using a 12-gene panel.	Moran O	Breast cancer research and treatment	2017	PMID: 27798748
Genetic modifiers of CHEK2*1100delC-associated breast cancer risk.	Muranen TA	Genetics in medicine : official journal of the American College of Medical Genetics	2017	PMID: 27711073
Breast cancer risk is similar for CHEK2 founder and non-founder mutation carriers.	Leedom TP	Cancer genetics	2016	PMID: 27751358
Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer.	Pritchard CC	The New England journal of medicine	2016	PMID: 27433846
Age- and Tumor Subtype-Specific Breast Cancer Risk Estimates for CHEK2*1100delC Carriers.	Schmidt MK	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2016	PMID: 27269948
Screening for germline BRCA1, BRCA2, TP53 and CHEK2 mutations in families at-risk for hereditary breast cancer identified in a population-based study from Southern Brazil.	Palmero EI	Genetics and molecular biology	2016	PMID: 27223485
Frequency of Germline Mutations in 25 Cancer Susceptibility Genes in a Sequential Series of Patients With Breast Cancer.	Tung N	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2016	PMID: 26976419
Increased Risk for Other Cancers in Addition to Breast Cancer for CHEK2*1100delC Heterozygotes Estimated From the Copenhagen General Population Study.	Näslund-Koch C	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2016	PMID: 26884562
CHEK2 mutations and the risk of papillary thyroid cancer.	Siołek M	International journal of cancer	2015	PMID: 25583358
CHEK2 (∗) 1100delC Mutation and Risk of Prostate Cancer.	Hale V	Prostate cancer	2014	PMID: 25431674
A risk of breast cancer in women - carriers of constitutional CHEK2 gene mutations, originating from the North - Central Poland.	Bąk A	Hereditary cancer in clinical practice	2014	PMID: 24713400
Genetic variants associated with colorectal cancer risk: comprehensive research synopsis, meta-analysis, and epidemiological evidence.	Ma X	Gut	2014	PMID: 23946381
CHEK2*1100delC homozygosity in the Netherlands--prevalence and risk of breast and lung cancer.	Huijts PE	European journal of human genetics : EJHG	2014	PMID: 23652375
BRCA1, TP53, and CHEK2 germline mutations in uterine serous carcinoma.	Pennington KP	Cancer	2013	PMID: 22811390
CHEK2*1100delC heterozygosity in women with breast cancer associated with early death, breast cancer-specific death, and increased risk of a second breast cancer.	Weischer M	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2012	PMID: 23109706
CHEK2 1100delC variant and breast cancer risk in Caucasians: a meta-analysis based on 25 studies with 29,154 cases and 37,064 controls.	Yang Y	Asian Pacific journal of cancer prevention : APJCP	2012	PMID: 22994785
Response to DNA damage of CHEK2 missense mutations in familial breast cancer.	Roeb W	Human molecular genetics	2012	PMID: 22419737
CHEK2*1100delC and risk of malignant melanoma: Danish and German studies and meta-analysis.	Weischer M	The Journal of investigative dermatology	2012	PMID: 21956126
CHEK2*1100delC homozygosity is associated with a high breast cancer risk in women.	Adank MA	Journal of medical genetics	2011	PMID: 22058428
Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing.	Walsh T	Proceedings of the National Academy of Sciences of the United States of America	2011	PMID: 22006311
Risk of breast cancer in women with a CHEK2 mutation with and without a family history of breast cancer.	Cybulski C	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2011	PMID: 21876083
Meta-analysis of CHEK2 1100delC variant and colorectal cancer susceptibility.	Xiang HP	European journal of cancer (Oxford, England : 1990)	2011	PMID: 21807500
Li-fraumeni syndrome.	Malkin D	Genes & cancer	2011	PMID: 21779515
A novel germline CHEK2 deletion truncating the kinase domain identified in a French family with high-risk of breast/ovarian cancer.	Escudie P	Breast cancer research and treatment	2010	PMID: 19768534
Mice with the CHEK2*1100delC SNP are predisposed to cancer with a strong gender bias.	Bahassi el M	Proceedings of the National Academy of Sciences of the United States of America	2009	PMID: 19805189
The contribution of CHEK2 to the TP53-negative Li-Fraumeni phenotype.	Ruijs MW	Hereditary cancer in clinical practice	2009	PMID: 19338683
CHEK2 1100delC and male breast cancer in the Netherlands.	Wasielewski M	Breast cancer research and treatment	2009	PMID: 18759107
Frequency of the CHEK2 1100delC mutation among women with breast cancer: an international study.	Zhang S	Cancer research	2008	PMID: 18381420
CHEK2*1100delC genotyping for clinical assessment of breast cancer risk: meta-analyses of 26,000 patient cases and 27,000 controls.	Weischer M	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2008	PMID: 18172190
Increased risk of breast cancer associated with CHEK2*1100delC.	Weischer M	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2007	PMID: 16880452
A large germline deletion in the Chek2 kinase gene is associated with an increased risk of prostate cancer.	Cybulski C	Journal of medical genetics	2006	PMID: 17085682
The CHEK2*1100delC allelic variant and risk of breast cancer: screening results from the Breast Cancer Family Registry.	Bernstein JL	Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology	2006	PMID: 16492927
Interaction between CHEK2*1100delC and other low-penetrance breast-cancer susceptibility genes: a familial study.	Johnson N	Lancet (London, England)	2005	PMID: 16257342
Germline CHEK2*1100delC mutations in breast cancer patients with multiple primary cancers.	Huang J	Journal of medical genetics	2004	PMID: 15520402
CHEK2 is a multiorgan cancer susceptibility gene.	Cybulski C	American journal of human genetics	2004	PMID: 15492928
Analysis of familial male breast cancer for germline mutations in CHEK2.	Sodha N	Cancer letters	2004	PMID: 15488637
Tumour characteristics and prognosis of breast cancer patients carrying the germline CHEK2*1100delC variant.	de Bock GH	Journal of medical genetics	2004	PMID: 15466005
CHEK2*1100delC and susceptibility to breast cancer: a collaborative analysis involving 10,860 breast cancer cases and 9,065 controls from 10 studies.	CHEK2 Breast Cancer Case-Control Consortium	American journal of human genetics	2004	PMID: 15122511
Limited relevance of the CHEK2 gene in hereditary breast cancer.	Dufault MR	International journal of cancer	2004	PMID: 15095295
A novel founder CHEK2 mutation is associated with increased prostate cancer risk.	Cybulski C	Cancer research	2004	PMID: 15087378
CHEK2*1100delC and male breast cancer risk in Israel.	Ohayon T	International journal of cancer	2004	PMID: 14648719
Role of CHEK2*1100delC in unselected series of non-BRCA1/2 male breast cancers.	Neuhausen S	International journal of cancer	2004	PMID: 14648718
CHEK2 1100delC is not a risk factor for male breast cancer population.	Syrjäkoski K	International journal of cancer	2004	PMID: 14648717
The CHEK2 1100delC mutation identifies families with a hereditary breast and colorectal cancer phenotype.	Meijers-Heijboer H	American journal of human genetics	2003	PMID: 12690581
Mutations in CHEK2 associated with prostate cancer risk.	Dong X	American journal of human genetics	2003	PMID: 12533788
A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer.	Vahteristo P	American journal of human genetics	2002	PMID: 12094328
Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations.	Meijers-Heijboer H	Nature genetics	2002	PMID: 11967536
Destabilization of CHK2 by a missense mutation associated with Li-Fraumeni Syndrome.	Lee SB	Cancer research	2001	PMID: 11719428
p53, CHK2, and CHK1 genes in Finnish families with Li-Fraumeni syndrome: further evidence of CHK2 in inherited cancer predisposition.	Vahteristo P	Cancer research	2001	PMID: 11479205
Characterization of tumor-associated Chk2 mutations.	Wu X	The Journal of biological chemistry	2001	PMID: 11053450
Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome.	Bell DW	Science (New York, N.Y.)	1999	PMID: 10617473
click to load more click to collapse

Text-mined citations for rs555607708 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_007194.4(CHEK2):c.1100del (p.Thr367fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs555607708 ...