ClinVar Genomic variation as it relates to human health
NM_007194.4(CHEK2):c.409C>T (p.Arg137Ter)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_007194.4(CHEK2):c.409C>T (p.Arg137Ter)
Variation ID: 182452 Accession: VCV000182452.53
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q12.1 22: 28725278 (GRCh38) [ NCBI UCSC ] 22: 29121266 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Dec 19, 2017 Feb 14, 2024 Jan 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_007194.4:c.409C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_009125.1:p.Arg137Ter nonsense NM_001005735.2:c.538C>T NP_001005735.1:p.Arg180Ter nonsense NM_001257387.2:c.-369C>T 5 prime UTR NM_001349956.2:c.409C>T NP_001336885.1:p.Arg137Ter nonsense NM_145862.2:c.409C>T NP_665861.1:p.Arg137Ter nonsense NC_000022.11:g.28725278G>A NC_000022.10:g.29121266G>A NG_008150.2:g.21589C>T LRG_302:g.21589C>T LRG_302t1:c.409C>T LRG_302p1:p.Arg137Ter - Protein change
- R137*, R180*
- Other names
- p.R137*:CGA>TGA
- Canonical SPDI
- NC_000022.11:28725277:G: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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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
Exome Aggregation Consortium (ExAC) 0.00003
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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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 |
3943 | 3999 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 16, 2023 | RCV000160452.13 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jan 29, 2024 | RCV000229303.18 | |
Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Dec 28, 2022 | RCV000254656.20 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000763477.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 21, 2017 | RCV001007871.5 | |
Pathogenic (1) |
criteria provided, single submitter
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May 27, 2021 | RCV001526967.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 10, 2022 | RCV002221501.6 | |
Pathogenic (1) |
no assertion criteria provided
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Jul 1, 2021 | RCV003162676.4 |
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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Pathogenic
(Oct 31, 2018)
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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
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000894259.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(Dec 21, 2017)
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criteria provided, single submitter
Method: clinical testing
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Congenital heart defects, multiple types, 3
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
maternal
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Genomic Medicine Lab, University of California San Francisco
Study: CSER
Accession: SCV001167572.1 First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020 |
Secondary finding: yes
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Pathogenic
(Oct 09, 2019)
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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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Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001449538.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 1
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Pathogenic
(May 27, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001737749.1
First in ClinVar: Jun 23, 2021 Last updated: Jun 23, 2021 |
Comment:
Variant summary: CHEK2 c.409C>T (p.Arg137X) 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.409C>T (p.Arg137X) 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 2.4e-05 in 251304 control chromosomes (gnomAD). c.409C>T has been reported in the literature in multiple individuals affected with breast cancer and/or ovarian cancer (Leedom_2016, Sun_2017, Moradian_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(May 17, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001134166.3
First in ClinVar: Jan 05, 2020 Last updated: Jan 01, 2022 |
Comment:
The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one … (more)
The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity. (less)
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Pathogenic
(Apr 10, 2022)
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criteria provided, single submitter
Method: clinical testing
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CHEK2-Related Cancer Susceptibility
Affected status: yes
Allele origin:
germline
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DASA
Accession: SCV002499412.1
First in ClinVar: Apr 16, 2022 Last updated: Apr 16, 2022 |
Comment:
The c.409C>T;p.(Arg137*) variant creates a premature translational stop signal in the CHEK2 gene. It is expected to result in an absent or disrupted protein product … (more)
The c.409C>T;p.(Arg137*) variant creates a premature translational stop signal in the CHEK2 gene. It is expected to result in an absent or disrupted protein product -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 182452; PMID: 33558524; 29356917) - PS4. The variant is present at low allele frequencies population databases (rs730881701 – gnomAD 0.0001315%; ABraOM 0.000427 frequency - https://abraom.ib.usp.br/) - PM2_supporting. In summary, the currently available evidence indicates that the variant is pathogenic. (less)
Number of individuals with the variant: 1
Sex: male
Geographic origin: Brazil
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Pathogenic
(Oct 28, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000274055.7
First in ClinVar: Feb 24, 2015 Last updated: Nov 29, 2022 |
Comment:
The p.R137* pathogenic mutation (also known as c.409C>T), located in coding exon 2 of the CHEK2 gene, results from a C to T substitution at … (more)
The p.R137* pathogenic mutation (also known as c.409C>T), located in coding exon 2 of the CHEK2 gene, results from a C to T substitution at nucleotide position 409. This changes the amino acid from an arginine to a stop codon within coding exon 2. This alteration has been reported in multiple patients undergoing multi-gene panel testing for personal history of breast cancer (Girard E et al. Int J Cancer, 2019 04;144:1962-1974; Akcay IM et al. Int J Cancer, 2021 01;148:285-295; Guglielmi C et al. Int J Mol Sci, 2021 Jul;22:(14); Moradian MM et al. Hum Genome Var, 2021 Feb;8:9). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Dec 28, 2022)
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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: SCV000211017.12
First in ClinVar: Oct 28, 2016 Last updated: Jan 07, 2023 |
Comment:
Nonsense 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; Not … (more)
Nonsense 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30322717, 32980694, 32805687, 32923877, 29922827, 35281821, 28888541, 27751358, 28724667, 28492532, 28779002, 29356917, 30303537, 29625052, 30287823, 32113160, 32658311, 31589614, 34426522, 33558524, 35418818, 34299313, 35710434) (less)
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Pathogenic
(Sep 18, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004217550.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jul 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002019289.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Aug 16, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000903769.4
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This variant changes 1 nucleotide in exon 3 of the CHEK2 gene, creating a premature translation stop signal. This variant is expected to result in … (more)
This variant changes 1 nucleotide in exon 3 of the CHEK2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast cancer (PMID: 28724667, 28779002, 29356917, 29922827, 30287823, 34299313). This variant has been identified in 6/251304 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)
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Pathogenic
(Jan 29, 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
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Invitae
Accession: SCV000289685.9
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg137*) 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.Arg137*) 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 (rs730881701, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 28724667). ClinVar contains an entry for this variant (Variation ID: 182452). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jun 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004045635.2
First in ClinVar: Oct 21, 2023 Last updated: Oct 28, 2023 |
Comment:
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
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Pathogenic
(Apr 08, 2020)
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no assertion criteria provided
Method: research
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Familial cancer of breast
Affected status: yes
Allele origin:
germline
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Center of Medical Genetics and Primary Health Care
Accession: SCV000987253.2
First in ClinVar: Mar 01, 2020 Last updated: Apr 15, 2020 |
Comment:
ACMG Guidelines 2015 criteria The CHEK2 variant p.Arg137Ter is in exon 3, in a kinase domain and in a mutation hotspot of 17 pathogenic variants … (more)
ACMG Guidelines 2015 criteria The CHEK2 variant p.Arg137Ter is in exon 3, in a kinase domain and in a mutation hotspot of 17 pathogenic variants (PM1 Pathogenic Moderate). This nonsense variant truncates the protein and thus makes it non-functional which is an established disease mechanism in disease (PVS1 Pathogenic Very Strong). The allele frequency in GnomAD exomes is 0.0000239 which is less the threshold 0.0001 for recessive gene CHEK2, and this variant is not found in GnomAD genomes (PM2 Pathogenic Moderate). 4 pathogenic predictions from DANN, EIGEN, FATHMM-MKL and MutationTaster versus no benign predictions support its deleterious effect (PP3 Pathogenic Supporting). In our study this variant was found in a 54-year-old female with unilateral breast cancer and a family history. Based on the evidence above we classified this variant as a Pathogenic. (less)
Age: 50-59 years
Sex: female
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Pathogenic
(-)
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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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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002035244.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
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Pathogenic
(-)
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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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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: SCV002037318.1 First in ClinVar: Dec 21, 2021 Last updated: Dec 21, 2021 |
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Pathogenic
(Jul 01, 2021)
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no assertion criteria provided
Method: research
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Gastric cancer
Affected status: unknown
Allele origin:
germline
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Laboratory for Genotyping Development, RIKEN
Accession: SCV002758248.1
First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023 |
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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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Helicobacter pylori, Homologous-Recombination Genes, and Gastric Cancer. | Usui Y | The New England journal of medicine | 2023 | PMID: 36988593 |
Detection of Germline Variants in 450 Breast/Ovarian Cancer Families with a Multi-Gene Panel Including Coding and Regulatory Regions. | Guglielmi C | International journal of molecular sciences | 2021 | PMID: 34299313 |
Germline mutational spectrum in Armenian breast cancer patients suspected of hereditary breast and ovarian cancer. | Moradian MM | Human genome variation | 2021 | PMID: 33558524 |
Germline pathogenic variant spectrum in 25 cancer susceptibility genes in Turkish breast and colorectal cancer patients and elderly controls. | Akcay IM | International journal of cancer | 2021 | PMID: 32658311 |
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 |
Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. | Momozawa Y | Nature communications | 2018 | PMID: 30287823 |
Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer. | Hu C | JAMA | 2018 | PMID: 29922827 |
Identification and analysis of CHEK2 germline mutations in Chinese BRCA1/2-negative breast cancer patients. | Fan Z | Breast cancer research and treatment | 2018 | PMID: 29356917 |
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 |
Germline Mutations in Cancer Susceptibility Genes in a Large Series of Unselected Breast Cancer Patients. | Sun J | Clinical cancer research : an official journal of the American Association for Cancer Research | 2017 | PMID: 28724667 |
Breast cancer risk is similar for CHEK2 founder and non-founder mutation carriers. | Leedom TP | Cancer genetics | 2016 | PMID: 27751358 |
Germline Mutations in Predisposition Genes in Pediatric Cancer. | Zhang J | The New England journal of medicine | 2015 | PMID: 26580448 |
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 |
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 |
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Text-mined citations for rs730881701 ...
HelpRecord last updated Mar 17, 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.