ClinVar Genomic variation as it relates to human health
NM_007194.4(CHEK2):c.410G>A (p.Arg137Gln)
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(1); Benign(1); Likely benign(14)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_007194.4(CHEK2):c.410G>A (p.Arg137Gln)
Variation ID: 128073 Accession: VCV000128073.52
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q12.1 22: 28725277 (GRCh38) [ NCBI UCSC ] 22: 29121265 (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 Jul 1, 2016 May 12, 2024 Feb 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_007194.4:c.410G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_009125.1:p.Arg137Gln missense NM_001005735.2:c.539G>A NP_001005735.1:p.Arg180Gln missense NM_001257387.2:c.-368G>A 5 prime UTR NM_001349956.2:c.410G>A NP_001336885.1:p.Arg137Gln missense NM_145862.2:c.410G>A NP_665861.1:p.Arg137Gln missense NC_000022.11:g.28725277C>T NC_000022.10:g.29121265C>T NG_008150.2:g.21590G>A LRG_302:g.21590G>A LRG_302t1:c.410G>A LRG_302p1:p.Arg137Gln O96017:p.Arg137Gln - Protein change
- R137Q, R180Q
- Other names
- p.R137Q:CGA>CAA
- Canonical SPDI
- NC_000022.11:28725276:C:T
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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
Help
The frequency of the allele represented by this VCV record.
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
The Genome Aggregation Database (gnomAD) 0.00012
Exome Aggregation Consortium (ExAC) 0.00021
The Genome Aggregation Database (gnomAD), exomes 0.00018
Trans-Omics for Precision Medicine (TOPMed) 0.00018
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
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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
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
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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
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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Likely benign (3) |
criteria provided, multiple submitters, no conflicts
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Mar 29, 2021 | RCV000116014.19 | |
Likely benign (5) |
criteria provided, multiple submitters, no conflicts
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Feb 1, 2024 | RCV000204285.24 | |
Benign/Likely benign (3) |
criteria provided, multiple submitters, no conflicts
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Jun 27, 2022 | RCV000254657.14 | |
Likely benign (6) |
criteria provided, multiple submitters, no conflicts
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Sep 1, 2023 | RCV000588933.37 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 27, 2017 | RCV001149532.12 | |
Likely benign (1) |
criteria provided, single submitter
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Jan 26, 2021 | RCV001798356.10 |
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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Likely benign
(Feb 16, 2015)
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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: SCV000537466.1
First in ClinVar: Mar 24, 2017 Last updated: Mar 24, 2017 |
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Likely benign
(Jan 26, 2021)
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criteria provided, single submitter
Method: clinical testing
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Breast and/or ovarian cancer
Affected status: unknown
Allele origin:
germline
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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV002043403.1
First in ClinVar: Jan 01, 2022 Last updated: Jan 01, 2022 |
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Likely benign
(Feb 18, 2019)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002070849.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
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Likely benign
(Mar 29, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002537429.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Benign
(Jun 27, 2022)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000698799.2
First in ClinVar: Mar 17, 2018 Last updated: Aug 08, 2022 |
Comment:
Variant summary: CHEK2 c.410G>A (p.Arg137Gln) results in a conservative amino acid change located in the Forkhead-associated (FHA) domain (IPR000253) of the encoded protein sequence. Four … (more)
Variant summary: CHEK2 c.410G>A (p.Arg137Gln) results in a conservative amino acid change located in the Forkhead-associated (FHA) domain (IPR000253) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 270830 control chromosomes, predominantly at a frequency of 0.00049 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 1.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in CHEK2 causing Breast Cancer phenotype (0.00031), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.410G>A has been reported in the literature in individuals affected with Breast Cancer (example, Bell_2007, Desrichard_2011, LeCalvez-Kelm_2011, Sodha_2002, Yorczyk_2014, Tung_2016, Momozawa_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer. At-least two co-occurrences with other pathogenic variant(s) have been observed at our laboratory (BRCA1 c.1960A>T, p.Lys654X; APC c.4647delA, p.Glu1550fs), providing supporting evidence for a benign role. Multiple publications report experimental evidence evaluating an impact on protein function (example, Bell_2007, Desrichard_2011, Roeb_2012, Sodha_2006, Delimitsou_2019). These results showed no damaging effect of this variant (expression, stability, kinase activity and yeast-based functional assay based on ability to repair MMS induced DNA damage and resume cell growth and proliferation). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with a majority consensus as likely benign. Based on the evidence outlined above, the variant was classified as benign. (less)
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Likely benign
(Jul 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: yes
Allele origin:
germline
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KCCC/NGS Laboratory, Kuwait Cancer Control Center
Accession: SCV004017380.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
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Likely benign
(Mar 09, 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: SCV004020196.1
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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Likely benign
(May 08, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000889335.4
First in ClinVar: Mar 17, 2018 Last updated: Jan 06, 2024 |
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Likely benign
(Feb 01, 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: SCV000260160.11
First in ClinVar: Jan 31, 2016 Last updated: Feb 14, 2024 |
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Likely benign
(Nov 16, 2018)
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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: SCV000183752.9
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
(Oct 13, 2017)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000149923.11
First in ClinVar: May 17, 2014 Last updated: Dec 19, 2017 |
Comment:
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more)
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
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Likely benign
(May 28, 2019)
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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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Mendelics
Accession: SCV001141372.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Uncertain significance
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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CHEK2-Related Cancer Susceptibility
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001310490.1
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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Likely benign
(Nov 11, 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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001470841.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
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Likely benign
(Mar 29, 2016)
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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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Counsyl
Accession: SCV000488438.2
First in ClinVar: Jul 01, 2016 Last updated: Dec 24, 2022 |
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Likely benign
(Sep 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001371418.19
First in ClinVar: Jul 16, 2020 Last updated: May 12, 2024 |
Comment:
CHEK2: BP4, BS3:Supporting
Number of individuals with the variant: 2
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Likely benign
(-)
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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: SCV001959278.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Likely benign
(-)
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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, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001931976.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Likely benign
(-)
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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: SCV001977684.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
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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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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 |
Functional characterization of CHEK2 variants in a Saccharomyces cerevisiae system. | Delimitsou A | Human mutation | 2019 | PMID: 30851065 |
Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. | Momozawa Y | Nature communications | 2018 | PMID: 30287823 |
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 |
Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. | Yurgelun MB | Gastroenterology | 2015 | PMID: 25980754 |
Use of panel tests in place of single gene tests in the cancer genetics clinic. | Yorczyk A | Clinical genetics | 2015 | PMID: 25318351 |
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 |
Response to DNA damage of CHEK2 missense mutations in familial breast cancer. | Roeb W | Human molecular genetics | 2012 | PMID: 22419737 |
CHEK2 contribution to hereditary breast cancer in non-BRCA families. | Desrichard A | Breast cancer research : BCR | 2011 | PMID: 22114986 |
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 |
Genetic and functional analysis of CHEK2 (CHK2) variants in multiethnic cohorts. | Bell DW | International journal of cancer | 2007 | PMID: 17721994 |
Rare germ line CHEK2 variants identified in breast cancer families encode proteins that show impaired activation. | Sodha N | Cancer research | 2006 | PMID: 16982735 |
CHEK2 variant I157T may be associated with increased breast cancer risk. | Kilpivaara O | International journal of cancer | 2004 | PMID: 15239132 |
CHEK2 variants in susceptibility to breast cancer and evidence of retention of the wild type allele in tumours. | Sodha N | British journal of cancer | 2002 | PMID: 12454775 |
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Text-mined citations for rs368570187 ...
HelpRecord last updated May 12, 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.