ClinVar Genomic variation as it relates to human health
NM_007194.4(CHEK2):c.1312G>T (p.Asp438Tyr)
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.
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.
Uncertain significance(14); Likely benign(9)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_007194.4(CHEK2):c.1312G>T (p.Asp438Tyr)
Variation ID: 128056 Accession: VCV000128056.76
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 22q12.1 22: 28695190 (GRCh38) [ NCBI UCSC ] 22: 29091178 (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 Jul 1, 2016 May 12, 2024 Mar 1, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_007194.4:c.1312G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_009125.1:p.Asp438Tyr missense NM_001005735.2:c.1441G>T NP_001005735.1:p.Asp481Tyr missense NM_001257387.2:c.649G>T NP_001244316.1:p.Asp217Tyr missense NM_001349956.2:c.1111G>T NP_001336885.1:p.Asp371Tyr missense NM_145862.2:c.1225G>T NP_665861.1:p.Asp409Tyr missense NC_000022.11:g.28695190C>A NC_000022.10:g.29091178C>A NG_008150.2:g.51677G>T LRG_302:g.51677G>T LRG_302t1:c.1312G>T LRG_302p1:p.Asp438Tyr - Protein change
- D438Y, D217Y, D371Y, D409Y, D481Y
- Other names
- p.D438Y:GAT>TAT
- Canonical SPDI
- NC_000022.11:28695189:C:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
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Global minor allele
frequency (GMAF) HelpThe 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.
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0.00020 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 0.00020
Exome Aggregation Consortium (ExAC) 0.00028
Trans-Omics for Precision Medicine (TOPMed) 0.00028
1000 Genomes Project 30x 0.00031
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00031
The Genome Aggregation Database (gnomAD) 0.00034
The Genome Aggregation Database (gnomAD), exomes 0.00039
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 | ||
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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. |
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CHEK2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3983 | 4037 |
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. |
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Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
|
Dec 14, 2020 | RCV000115996.26 | |
Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
|
Jan 31, 2024 | RCV000199565.30 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Aug 28, 2023 | RCV000200982.22 | |
Uncertain significance (1) |
criteria provided, single submitter
|
May 23, 2017 | RCV000515311.7 | |
Conflicting interpretations of pathogenicity (12) |
criteria provided, conflicting classifications
|
Mar 1, 2024 | RCV000587890.43 | |
Uncertain significance (2) |
criteria provided, single submitter
|
Apr 27, 2017 | RCV001147975.10 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Oct 12, 2019 | RCV001294021.6 | |
Likely benign (1) |
no assertion criteria provided
|
- | RCV001269492.6 | |
Uncertain significance (1) |
no assertion criteria provided
|
- | RCV001356041.6 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Jan 9, 2024 | RCV003483481.1 | |
Likely benign (1) |
criteria provided, single submitter
|
Jan 23, 2024 | RCV003492502.1 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Feb 27, 2023 | RCV001798350.8 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Jan 30, 2024 | RCV004528803.1 | |
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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. |
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Uncertain significance
(Aug 01, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: yes
Allele origin:
germline
|
GeneKor MSA
Accession: SCV000821989.1
First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018 |
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Uncertain significance
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
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CHEK2-Related Cancer Susceptibility
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001308835.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
|
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Uncertain significance
(Oct 12, 2019)
|
criteria provided, single submitter
Method: clinical testing
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Li-Fraumeni syndrome 2
Affected status: yes
Allele origin:
unknown
|
Baylor Genetics
Study: CSER-TexasKidsCanSeq
Accession: SCV001482780.1 First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021 |
Comment:
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
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Likely benign
(Nov 22, 2022)
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criteria provided, single submitter
Method: research
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Familial cancer of breast
Affected status: yes, no
Allele origin:
germline
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Research Unit of Translational Medicine, University of Oulu
Accession: SCV003930315.1
First in ClinVar: Jun 17, 2023 Last updated: Jun 17, 2023 |
Comment:
The frequency of p.Asp438Tyr variant in CHEK2 among Northern Finnish breast cancer cases was 0.6% (14/2284) and nearly equal in geographically matched healthy population controls … (more)
The frequency of p.Asp438Tyr variant in CHEK2 among Northern Finnish breast cancer cases was 0.6% (14/2284) and nearly equal in geographically matched healthy population controls (0.8%, 10/1299) in a study by Kumpula et al. (2023). Similar carrier frequencies in the studied cases and the general population argue against association of CHEK2 p.Asp438Tyr with increased breast cancer risk. Therefore the variant can be classified as likely benign. (less)
Observation 1:
Number of individuals with the variant: 14
Sex: female
Geographic origin: Northern Finnish
Observation 2:
Number of individuals with the variant: 10
Sex: mixed
Geographic origin: Northern Finnish
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Uncertain significance
(Sep 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000601150.4
First in ClinVar: Mar 08, 2017 Last updated: Jan 06, 2024 |
Comment:
In the published literature, this variant has been reported in individuals with breast cancer (PMIDs: 36653541 (2023), 35886069 (2022), 33558524 (2021), 33134171 (2020), 31050813 (2019), … (more)
In the published literature, this variant has been reported in individuals with breast cancer (PMIDs: 36653541 (2023), 35886069 (2022), 33558524 (2021), 33134171 (2020), 31050813 (2019), 29484706 (2018), 29335925 (2018), 28779002 (2017), 25186627 (2015), 24390236 (2014), 21244692 (2011)), endometrial cancer (PMID:27443514 (2016)), colorectal cancer (PMID: 29987844 (2018)), and prostate cancer (PMIDs: 18571837 (2008), 17721994 (2007), 14612911 (2003)). This variant has also been identified in healthy control individuals (PMIDs: 36653541 (2023), 31050813 (2019), 30303537 (2019), 28779002 (2017), 21244692 (2011), 17721994 (2007)), and reported to co-occur with deleterious variants in the MRE11 and MSH2 genes (PMIDs: 33134171 (2020), 27443514 (2016)). Case-control studies suggest this variant is associated with prostate cancer risk but not breast cancer risk (PMIDs: 27595995 (2016), 36653541 (2023)). In addition, experimental studies indicate this variant has neutral to intermediate effects on CHEK2 protein function (PMIDs: 34903604 (2022), 31050813 (2019), 30851065 (2019), 17721994 (2007)). The frequency of this variant in the general population, 0.0013 (32/25122 chromosomes in European (Finnish) subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
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Uncertain significance
(Feb 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
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Breast and/or ovarian cancer
Affected status: unknown
Allele origin:
germline
|
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV002043391.2
First in ClinVar: Jan 01, 2022 Last updated: Feb 04, 2024 |
|
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Likely benign
(Apr 26, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000149905.20
First in ClinVar: May 17, 2014 Last updated: Feb 14, 2024 |
Comment:
Published functional studies are inconclusive/conflicting: demonstrates intermediate/reduced kinase activity in some studies while others, including a human-cell based assay, show activity comparable to wildtype (Bell … (more)
Published functional studies are inconclusive/conflicting: demonstrates intermediate/reduced kinase activity in some studies while others, including a human-cell based assay, show activity comparable to wildtype (Bell et al., 2007; Delimitsou et al., 2019; Kleiblova et al., 2019; Boonen et al., 2022); Observed in individuals with a personal and/or family history of breast, prostate, or colorectal cancer (Seppala et al., 2003; Bell et al., 2007; Tischkowitz et al., 2008; Baloch et al., 2014; Tung et al., 2015; Kayser et al., 2018; Fanale et al., 2020; Grasel et al., 2020; Moradian et al., 2021; Paduano et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 14612911, 15087378, 28828701, 28776603, 28873162, 24390236, 17721994, 18571837, 23960188, 21244692, 27067391, 26787654, 28553140, 25186627, 27153395, 27498913, 27878467, 28452373, 19768534, 29335925, 27595995, 27443514, 29987844, 29484706, 30344923, 28301460, 30851065, 29875428, 29522266, 31050813, 31398194, 31159747, 28779002, 31220302, 33134171, 33322746, 32854451, 33558524, 27009842, 32906215, 30613976, 27535533, 34903604, 34347074, 22419737, 19782031, 35886069, 33840814) (less)
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Likely benign
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000254923.12
First in ClinVar: Oct 11, 2015 Last updated: Feb 14, 2024 |
|
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Uncertain significance
(Jan 30, 2024)
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criteria provided, single submitter
Method: clinical testing
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CHEK2-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV000806866.3
First in ClinVar: Sep 13, 2018 Last updated: Mar 16, 2024 |
Comment:
The CHEK2 c.1312G>T variant is predicted to result in the amino acid substitution p.Asp438Tyr. This variant has been reported in individuals with a history of … (more)
The CHEK2 c.1312G>T variant is predicted to result in the amino acid substitution p.Asp438Tyr. This variant has been reported in individuals with a history of breast, prostate, and colorectal cancers; but has also been reported in unaffected control individuals (Baloch et al. 2014. PubMed ID: 24390236; Supplementary Table 1, Le Calvez-Kelm et al. 2011. PubMed ID: 21244692; Tischkowitz et al. 2008. PubMed ID: 18571837; Kleiblova et al. 2019. PubMed ID: 31050813; Moradian et al. 2021. PubMed ID: 33558524; Biscaglia et al. 2022. PubMed ID: 34347074). Functional studies have shown this variant impacts CHEK2 kinase activity by 70% when compared to wild-type protein; however, it is unclear whether this is sufficient to contribute to disease (Bell et al. 2007. PubMed ID: 17721994). This variant is reported in 0.13% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-29091178-C-A). It has conflicting interpretations in ClinVar ranging from likely benign to uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/128056/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
|
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Uncertain significance
(May 23, 2017)
|
criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Malignant tumor of prostate Bone osteosarcoma Li-Fraumeni syndrome 2
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000611451.1
First in ClinVar: Nov 11, 2017 Last updated: Nov 11, 2017 |
|
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Likely benign
(Aug 30, 2019)
|
criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000537526.4
First in ClinVar: Sep 24, 2016 Last updated: Mar 25, 2020 |
|
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Uncertain significance
(-)
|
criteria provided, single submitter
Method: research
|
Hereditary cancer-predisposing syndrome
Affected status: yes
Allele origin:
paternal
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Department of Pediatric Oncology, Hematology and Clinical Immunology, University Clinics Duesseldorf
Accession: SCV001482297.1
First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021 |
Family history: no
|
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Uncertain significance
(Jan 11, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: no
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV002070844.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
|
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Uncertain significance
(Aug 12, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000489071.2
First in ClinVar: Jul 01, 2016 Last updated: Dec 24, 2022 |
|
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Uncertain significance
(Nov 03, 2021)
|
criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
|
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002009508.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
|
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Likely benign
(Mar 09, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004020177.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic … (more)
This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. (less)
|
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Uncertain significance
(Aug 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002761098.3
First in ClinVar: Dec 17, 2022 Last updated: Aug 18, 2023 |
|
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Likely benign
(Aug 28, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000698770.5
First in ClinVar: Mar 17, 2018 Last updated: Oct 04, 2023 |
Comment:
Variant summary: CHEK2 c.1312G>T (p.Asp438Tyr) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Four … (more)
Variant summary: CHEK2 c.1312G>T (p.Asp438Tyr) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0004 in 261860 control chromosomes, predominantly at a frequency of 0.00046 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.5- fold the estimated maximal expected allele frequency for a pathogenic variant in CHEK2 causing Hereditary Breast and Ovarian Cancer phenotype (0.00031), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. However, the frequency in gnomAD and the cases reported in the literature may not be accurate due to the sequencing technology used being unable to distinguish between CHEK2 and its multiple overlapping pseudogenes. This variant has also been reported among 7 women older than 70 years who have never had cancer as reported in the FLOSSIES database. c.1312G>T, has been reported in the literature in individuals affected with Breast and/or Ovarian Cancer, but also in controls and in a family where it did not segregate with disease (examples- Baloch_2013, Bell_2007, LeCalvez-Kelm_2011, Seppala_2003, Tischkowitz_2008, Young_2016, Yadav_2016, Tung_2015, Maxwell_2016, Fostira_2018, Scarpetta_2019). Case control approaches indicated no significant risk association for breast cancer, but a slightly elevated risk for prostate cancer (Le Calvez-Kelm_2011, Southey_2016). These data thus do not allow any conclusion about variant significance. At-least one co-occurrence with another pathogenic variant has been reported (MSH2 c.1697del, p.Asn566IlefsX24), providing supporting evidence for a benign role (Ring_2016). In a mammalian cell based kinase-assay the variant protein showed about 70% reduction in activity (Bell_2007), whereas in a yeast based DNA-damage assay the variant showed similar function to the wild type supporting a benign outcome (Delimitsou_2019). The following publications have been ascertained in the context of this evaluation (PMID: 24390236, 17721994, 15087378, 30851065, 31811167, 29335925, 30303537, 33134171, 29484706, 25231023, 29987844, 21244692, 30322893, 27153395, 33558524, 27443514, 31512090, 14612911, 27595995, 18571837, 31159747, 25186627, 29875428, 27878467, 31214250, 26787654, 28828701, 23960188). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and cited the variant as uncertain significance (n=15) and likely benign (n=5). Based on the evidence outlined above, the variant was classified as likely benign. (less)
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Uncertain significance
(Jan 09, 2024)
|
criteria provided, single submitter
Method: curation
|
Hereditary breast ovarian cancer syndrome
Affected status: not provided
Allele origin:
germline
|
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne
Accession: SCV004231867.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
Results from functional assays as well as predictions are contradictory. According to the ACMG standard criteria we chose this criterium: BS1 (strong benign): gnomAD v3.1.2 … (more)
Results from functional assays as well as predictions are contradictory. According to the ACMG standard criteria we chose this criterium: BS1 (strong benign): gnomAD v3.1.2 (non-cancer): AF: 0.0005092 + 1 x hom (less)
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Likely benign
(Jan 23, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV000839460.3
First in ClinVar: Oct 10, 2018 Last updated: Feb 04, 2024 |
|
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Uncertain significance
(Jun 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV004235063.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
|
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Likely benign
(Dec 14, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000172942.9
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Likely benign
(Mar 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV000892301.17
First in ClinVar: Mar 31, 2019 Last updated: May 12, 2024 |
Comment:
CHEK2: BP1, BP4, BS2
Number of individuals with the variant: 6
|
|
Uncertain significance
(-)
|
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: SCV001808572.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
|
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Uncertain significance
(-)
|
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: SCV001952270.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
Breast Cancer
Affected status: yes
Allele origin:
germline
|
Center of Medical Genetics and Primary Health Care
Accession: SCV001449146.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
|
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Uncertain significance
(Apr 08, 2020)
|
no assertion criteria provided
Method: research
|
Familial cancer of breast
Affected status: yes
Allele origin:
germline
|
Center of Medical Genetics and Primary Health Care
Accession: SCV000987292.3
First in ClinVar: Dec 17, 2019 Last updated: May 04, 2020 |
Comment:
ACMG Guidelines 2015 criteria PM1 Pathogenic Moderate: Pkinase domain (M265-529L aa) which contains the catalytic function of protein kinases. Hot-spot has 21 non-VUS coding variants … (more)
ACMG Guidelines 2015 criteria PM1 Pathogenic Moderate: Pkinase domain (M265-529L aa) which contains the catalytic function of protein kinases. Hot-spot has 21 non-VUS coding variants (7 pathogenic and 14 benign), pathogenicity = 33.3%, proximity score 3.967 > threshold 2.472. PP1 Pathogenic Supporting: Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease. PP2 Pathogenic Supporting: 30 out of 48 non-VUS missense variants in gene CHEK2 are pathogenic = 62.5% > threshold of 51.0%, and 308 out of 1,604 clinically reported variants in gene CHEK2 are pathogenic = 19.2% > threshold of 12.0%. PP1 Pathogenic Supporting: 2 patients are sibs (sisters) who share the same variant. BP4 Benign Supporting: 6 benign predictions from DEOGEN2, EIGEN, MVP, MutationAssessor, PrimateAI and REVEL vs 5 pathogenic predictions from DANN, FATHMM-MKL, M-CAP, MutationTaster and SIFT and the position is not conserved." Therefore, this variant was classified as a Variant of Unknown Significance. (less)
Number of individuals with the variant: 2
Age: 44-51 years
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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Carcinoma of colon
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001551095.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The CHEK2 p.Asp438Tyr variant was identified in 4 of 1332 proband chromosomes (frequency: 0.003) from Pakistani, Finnish, Polish and Ashkenazi Jewish individuals or families with … (more)
The CHEK2 p.Asp438Tyr variant was identified in 4 of 1332 proband chromosomes (frequency: 0.003) from Pakistani, Finnish, Polish and Ashkenazi Jewish individuals or families with breast, early onset breast and prostate, or hereditary prostate cancer and was not identified in 590 control chromosomes from healthy individuals (Baloch 2014, Seppala 2003, Tischkowitz 2008, Bell 2007). The variant was identified in dbSNP (ID: rs200050883) “With Uncertain significance allele”, ClinVar (classified as uncertain significance by GeneDx, Ambry Genetics, Invitae, Counsyl, and Color Genomics), and the Zhejiang Colon Cancer Database (14x, co-occurring with CHEK2 c.1100delC). The variant was not identified in Cosmic. The variant was identified in control databases in 108 of 276806 chromosomes at a frequency of 0.0004 (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations: European in 57 of 126326 chromosomes (frequency: 0.0005), Finnish in 33 of 25792 chromosomes (frequency: 0.001), African in 3 of 24032 chromosomes (frequency: 0.0001), Other in 4 of 6456 chromosomes (frequency: 0.0006), Latino in 2 of 34404 chromosomes (frequency: 0.00006), and South Asian in 9 of 30776 chromosomes (frequency: 0.0003). The variant occurs in the catalytic domain of the CHEK2 protein and in vitro analysis of kinase activity showed the variant had a 70% decrease in activity compared to wildtype (Baloch 2014, Bell 2007). The p.Asp438 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Tyr variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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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: SCV001905700.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001962749.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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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: SCV001980184.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002036312.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
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not provided
(-)
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no classification provided
Method: phenotyping only
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Not Provided
Affected status: unknown
Allele origin:
unknown
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GenomeConnect, ClinGen
Accession: SCV000986776.3
First in ClinVar: Aug 31, 2019 Last updated: Feb 11, 2022 |
Comment:
The variant was identified in multiple GenomeConnect participants. Variant interpreted as Uncertain significance and reported on 03-29-2018 by Lab or GTR ID Northwell Health Laboratories. … (more)
The variant was identified in multiple GenomeConnect participants. Variant interpreted as Uncertain significance and reported on 03-29-2018 by Lab or GTR ID Northwell Health Laboratories. Variant interpreted as Uncertain significance and reported, most recently, on 12/04/2018 by GTR ID Credit Valley Hospital Department of Laboratory Medicine. 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:
Breast carcinoma (present)
Indication for testing: Diagnostic|Family Testing
Age: 40-49 years
Sex: female
Method: Sanger Sequencing
Testing laboratory: Northwell Health Laboratories
Date variant was reported to submitter: 2018-03-29
Testing laboratory interpretation: Uncertain significance
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Tinnitus (present) , Abnormal curvature of the vertebral column (present) , Cardiac arrhythmia (present) , Breast carcinoma (present)
Age: 50-59 years
Sex: female
Testing laboratory: Genetics Laboratory, Trillium Health Partners,Trillium Health Partners, Credit Valley Hospital Site
Date variant was reported to submitter: 2018-05-18
Testing laboratory interpretation: Uncertain significance
Observation 3:
Number of individuals with the variant: 1
Clinical Features:
Breast carcinoma (present) , Periodontitis (present)
Age: 40-49 years
Sex: female
Testing laboratory: Genetics Laboratory, Trillium Health Partners,Trillium Health Partners, Credit Valley Hospital Site
Date variant was reported to submitter: 2018-09-21
Testing laboratory interpretation: Uncertain significance
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not provided
(-)
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no classification provided
Method: phenotyping only
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CHEK2-Related Cancer Susceptibility
Affected status: unknown
Allele origin:
unknown
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GenomeConnect - Invitae Patient Insights Network
Accession: SCV004228603.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
Variant interpreted as Likely benign and reported on 04-04-2017 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the … (more)
Variant interpreted as Likely benign and reported on 04-04-2017 by Lab Invitae. 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)
Clinical Features:
Abnormal skull morphology (present) , Obesity (present) , Hyperthyroidism (present)
Indication for testing: Diagnostic
Age: 50-59 years
Sex: female
Method: Gene Panel Sequencing
Testing laboratory: Invitae
Date variant was reported to submitter: 2017-04-04
Testing laboratory interpretation: Likely benign
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Evaluating the role of CHEK2 p.(Asp438Tyr) allele in inherited breast cancer predisposition. | Kumpula TA | Familial cancer | 2023 | DOI: 10.1007/s10689-023-00327-2 |
Evaluating the role of CHEK2 p.(Asp438Tyr) allele in inherited breast cancer predisposition. | Kumpula TA | Familial cancer | 2023 | PMID: 36653541 |
Germline Testing in a Cohort of Patients at High Risk of Hereditary Cancer Predisposition Syndromes: First Two-Year Results from South Italy. | Paduano F | Genes | 2022 | PMID: 35886069 |
Functional Analysis Identifies Damaging CHEK2 Missense Variants Associated with Increased Cancer Risk. | Boonen RACM | Cancer research | 2022 | PMID: 34903604 |
Germline mutational spectrum in Armenian breast cancer patients suspected of hereditary breast and ovarian cancer. | Moradian MM | Human genome variation | 2021 | PMID: 33558524 |
Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
Using Co-segregation and Loss of Heterozygosity Analysis to Define the Pathogenicity of Unclassified Variants in Hereditary Breast Cancer Patients. | Grasel RS | Frontiers in oncology | 2020 | PMID: 33134171 |
Results of multigene panel testing in familial cancer cases without genetic cause demonstrated by single gene testing. | Dominguez-Valentin M | Scientific reports | 2019 | PMID: 31811167 |
Germline investigation in male breast cancer of DNA repair genes by next-generation sequencing. | Scarpitta R | Breast cancer research and treatment | 2019 | PMID: 31512090 |
Germline CHEK2 Gene Mutations in Hereditary Breast Cancer Predisposition - Mutation Types and their Biological and Clinical Relevance. | Kleiblová P | Klinicka onkologie : casopis Ceske a Slovenske onkologicke spolecnosti | 2019 | PMID: 31409080 |
Prognostic Significance of CHEK2 Mutation in Progression of Breast Cancer. | Ansari N | Laboratory medicine | 2019 | PMID: 31220302 |
Revisiting Non-BRCA1/2 Familial Whole Exome Sequencing Datasets Implicates NCK1 as a Cancer Gene. | Yin J | Frontiers in genetics | 2019 | PMID: 31214250 |
Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. | Tsaousis GN | BMC cancer | 2019 | PMID: 31159747 |
Identification of deleterious germline CHEK2 mutations and their association with breast and ovarian cancer. | Kleiblova P | International journal of cancer | 2019 | PMID: 31050813 |
Functional characterization of CHEK2 variants in a Saccharomyces cerevisiae system. | Delimitsou A | Human mutation | 2019 | PMID: 30851065 |
Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing. | Girard E | International journal of cancer | 2019 | PMID: 30303537 |
The impact of variant classification on the clinical management of hereditary cancer syndromes. | Turner SA | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 29875428 |
Identification of therapeutic targets in chordoma through comprehensive genomic and transcriptomic analyses. | Liang WS | Cold Spring Harbor molecular case studies | 2018 | PMID: 30322893 |
Copy number variation analysis and targeted NGS in 77 families with suspected Lynch syndrome reveals novel potential causative genes. | Kayser K | International journal of cancer | 2018 | PMID: 29987844 |
Identification of a novel truncating mutation in PALB2 gene by a multigene sequencing panel for mutational screening of breast cancer risk-associated and related genes. | Guacci A | Journal of clinical laboratory analysis | 2018 | PMID: 29484706 |
Germline deleterious mutations in genes other than BRCA2 are infrequent in male breast cancer. | Fostira F | Breast cancer research and treatment | 2018 | PMID: 29335925 |
Inherited predisposition to breast and ovarian cancer in non-Jewish populations in Israel. | Zidan J | Breast cancer research and treatment | 2017 | PMID: 28828701 |
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 |
Outcomes of retesting BRCA negative patients using multigene panels. | Yadav S | Familial cancer | 2017 | PMID: 27878467 |
The transfer of multigene panel testing for hereditary breast and ovarian cancer to healthcare: What are the implications for the management of patients and families? | Eliade M | Oncotarget | 2017 | PMID: 27779110 |
PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS. | Southey MC | Journal of medical genetics | 2016 | PMID: 27595995 |
Germline multi-gene hereditary cancer panel testing in an unselected endometrial cancer cohort. | Ring KL | Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc | 2016 | PMID: 27443514 |
Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer. | Maxwell KN | American journal of human genetics | 2016 | PMID: 27153395 |
Multigene testing of moderate-risk genes: be mindful of the missense. | Young EL | Journal of medical genetics | 2016 | PMID: 26787654 |
Targeted genomic analysis of Müllerian adenosarcoma. | Howitt BE | The Journal of pathology | 2015 | PMID: 25231023 |
Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. | Tung N | Cancer | 2015 | PMID: 25186627 |
Development and validation of a new algorithm for the reclassification of genetic variants identified in the BRCA1 and BRCA2 genes. | Pruss D | Breast cancer research and treatment | 2014 | PMID: 25085752 |
Missense mutations (p.H371Y, p.D438Y) in gene CHEK2 are associated with breast cancer risk in women of Balochistan origin. | Baloch AH | Molecular biology reports | 2014 | PMID: 24390236 |
DNA repair genes are selectively mutated in diffuse large B cell lymphomas. | de Miranda NF | The Journal of experimental medicine | 2013 | PMID: 23960188 |
Rare, evolutionarily unlikely missense substitutions in CHEK2 contribute to breast cancer susceptibility: results from a breast cancer family registry case-control mutation-screening study. | Le Calvez-Kelm F | Breast cancer research : BCR | 2011 | PMID: 21244692 |
Identification and characterization of novel SNPs in CHEK2 in Ashkenazi Jewish men with prostate cancer. | Tischkowitz MD | Cancer letters | 2008 | PMID: 18571837 |
Genetic and functional analysis of CHEK2 (CHK2) variants in multiethnic cohorts. | Bell DW | International journal of cancer | 2007 | PMID: 17721994 |
CHEK2 variants associate with hereditary prostate cancer. | Seppälä EH | British journal of cancer | 2003 | PMID: 14612911 |
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Text-mined citations for rs200050883 ...
HelpRecord last updated May 19, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.