Submissions for variant NM_000251.3(MSH2):c.1798G>T (p.Ala600Ser)

dbSNP: rs587778526

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000543103	SCV000625319	benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001804848	SCV002051868	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-02	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with serine at codon 600 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer but has been reported in healthy individuals (PMID: 24728327). This variant has been identified in 1/251464 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.
Ambry Genetics	RCV001804848	SCV002716899	likely benign	Hereditary cancer-predisposing syndrome	2023-08-28	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.
GeneDx	RCV003325461	SCV004031832	uncertain significance	not provided	2023-08-31	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in healthy individuals undergoing whole genome sequencing (Bodian et al., 2014); Published functional studies suggest a neutral effect: demonstrated sensitivity to 6-TG and mismatch repair (MMR) function similar to wild-type (Jia et al., 2020); This variant is associated with the following publications: (PMID: 18822302, 9774676, 21120944, 24728327, 33357406)
PreventionGenetics, part of Exact Sciences	RCV004530024	SCV004115527	uncertain significance	MSH2-related disorder	2023-01-13	criteria provided, single submitter	clinical testing	The MSH2 c.1798G>T variant is predicted to result in the amino acid substitution p.Ala600Ser. To our knowledge, this variant has not been reported in the literature in individuals with MSH2-related disorders. This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-47702202-G-T). It is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/134844). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
ITMI	RCV000121563	SCV000085757	not provided	not specified	2013-09-19	no assertion provided	reference population