Submissions for variant NM_007194.4(CHEK2):c.74T>C (p.Val25Ala)

gnomAD frequency: 0.00001  dbSNP: rs587780188

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001704016	SCV000149938	likely benign	not provided	2019-08-14	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21244692, 22006311, 22419737, 26787654, 29458332)
Invitae	RCV000233411	SCV000289703	uncertain significance	Familial cancer of breast	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 25 of the CHEK2 protein (p.Val25Ala). This variant is present in population databases (rs587780188, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer, colon cancer, ovarian, peritoneal, or fallopian tube cancer (PMID: 21244692, 22006311, 29458332). ClinVar contains an entry for this variant (Variation ID: 128085). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change does not substantially affect CHEK2 function (PMID: 22006311, 22419737). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl	RCV000233411	SCV000489591	uncertain significance	Familial cancer of breast	2016-10-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000571943	SCV000665182	likely benign	Hereditary cancer-predisposing syndrome	2018-04-21	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.
Color Diagnostics, LLC DBA Color Health	RCV000571943	SCV000905157	likely benign	Hereditary cancer-predisposing syndrome	2016-09-29	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000233411	SCV004020228	uncertain significance	Familial cancer of breast	2023-03-09	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Genetic Services Laboratory, University of Chicago	RCV003150946	SCV003839358	uncertain significance	not specified	2022-09-07	no assertion criteria provided	clinical testing	DNA sequence analysis of the CHEK2 gene demonstrated a sequence change, c.74T>C, in exon 2 that results in an amino acid change, p.Val25Ala. This sequence change has been previously described in individuals with breast cancer, colorectal cancer, ovarian, peritoneal, or fallopian tube cancer (PMID: 21244692, 22006311, 29458332). Functional assays have shown that it does not impact CHEK2 function (PMID: 22006311, 22419737). This sequence change has been described in the gnomAD database with a frequency of 0.01% in the European subpopulation (dbSNP rs587780188). The p.Val25Ala change affects a poorly conserved amino acid residue located in a domain of the CHEK2 protein that is not known to be functional. The p.Val25Ala substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidences, the clinical significance of the p.Val25Ala change remains unknown at this time.