Submissions for variant NM_000251.3(MSH2):c.1967A>G (p.Tyr656Cys)

gnomAD frequency: 0.00001  dbSNP: rs185356145

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000213193	SCV000276157	likely benign	Hereditary cancer-predisposing syndrome	2021-11-08	criteria provided, single submitter	clinical testing	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.
Invitae	RCV000791407	SCV000548273	benign	Hereditary nonpolyposis colorectal neoplasms	2023-08-03	criteria provided, single submitter	clinical testing
Mendelics	RCV000477485	SCV000837842	uncertain significance	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000213193	SCV000906777	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-08	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 656 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 3/251366 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985799	SCV001134347	uncertain significance	not provided	2019-01-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000985799	SCV001823807	uncertain significance	not provided	2021-05-05	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 31569399)
PreventionGenetics, part of Exact Sciences	RCV004532791	SCV004117504	uncertain significance	MSH2-related disorder	2022-11-28	criteria provided, single submitter	clinical testing	The MSH2 c.1967A>G variant is predicted to result in the amino acid substitution p.Tyr656Cys. To our knowledge, this variant has not been reported in individuals with MSH2-related disorders in the literature. This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-47702371-A-G) and is interpreted as uncertain significance and likely benign in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/232107/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV003469050	SCV004196261	uncertain significance	Lynch syndrome 1	2023-09-08	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000477485	SCV004825106	uncertain significance	Lynch syndrome	2023-10-27	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 656 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 3/251366 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.