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

gnomAD frequency: 0.00012  dbSNP: rs368570187

Total submissions: 19

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	This alteration is classified as likely benign based on a combination of the following: 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.
Invitae	RCV000204285	SCV000260160	likely benign	Familial cancer of breast	2024-02-01	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	2023-05-08	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	2023-09-01	criteria provided, single submitter	clinical testing	CHEK2: BP4, BS3:Supporting
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
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000204285	SCV004017380	likely benign	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000204285	SCV004020196	likely benign	Familial cancer of breast	2023-03-09	criteria provided, single submitter	clinical testing	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].
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