ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.410G>A (p.Arg137Gln)

gnomAD frequency: 0.00013  dbSNP: rs368570187
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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000254657 SCV000149923 likely benign not specified 2017-10-13 criteria provided, single submitter clinical testing 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.
Ambry Genetics RCV000116014 SCV000183752 likely benign Hereditary cancer-predisposing syndrome 2018-11-16 criteria provided, single submitter clinical testing In silico models in agreement (benign);Intact protein function observed in appropriate functional assay(s)
Invitae RCV000204285 SCV000260160 likely benign Familial cancer of breast 2021-12-17 criteria provided, single submitter clinical testing
Counsyl RCV000204285 SCV000488438 likely benign Familial cancer of breast 2016-03-29 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000116014 SCV000537466 likely benign Hereditary cancer-predisposing syndrome 2015-02-16 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000254657 SCV000698799 benign not specified 2022-06-27 criteria provided, single submitter clinical testing 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588933 SCV000889335 likely benign not provided 2019-07-16 criteria provided, single submitter clinical testing
Mendelics RCV000204285 SCV001141372 likely benign Familial cancer of breast 2019-05-28 criteria provided, single submitter clinical testing
Illumina Laboratory Services,Illumina RCV001149532 SCV001310490 uncertain significance CHEK2-Related Cancer Susceptibility 2017-04-27 criteria provided, single submitter clinical testing 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.
CeGaT Center for Human Genetics Tuebingen RCV000588933 SCV001371418 likely benign not provided 2020-06-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000588933 SCV001470841 likely benign not provided 2019-11-11 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001798356 SCV002043403 likely benign Breast and/or ovarian cancer 2021-01-26 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000254657 SCV002070849 likely benign not specified 2019-02-18 criteria provided, single submitter clinical testing
Sema4,Sema4 RCV000116014 SCV002537429 likely benign Hereditary cancer-predisposing syndrome 2021-03-29 criteria provided, single submitter curation
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000588933 SCV001931976 likely benign not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000588933 SCV001959278 likely benign not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000588933 SCV001977684 likely benign not provided no assertion criteria provided clinical testing

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