Submissions for variant NM_000251.3(MSH2):c.2083G>A (p.Val695Met)

dbSNP: rs772491283

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000781997	SCV000920454	pathogenic	Lynch syndrome	2018-10-18	reviewed by expert panel	curation	Multifactorial likelihood analysis posterior probability > 0.99 (0.998)
Ambry Genetics	RCV001014369	SCV001175067	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-09-16	criteria provided, single submitter	clinical testing	The p.V695M variant (also known as c.2083G>A), located in coding exon 13 of the MSH2 gene, results from a G to A substitution at nucleotide position 2083. The valine at codon 695 is replaced by methionine, an amino acid with highly similar properties. This alteration has been classified as pathogenic using the following lines of evidence: in silico prediction models, segregation with disease, and clinical phenotype which includes tumor characteristics (Thompson BA et al. Hum. Mutat. 2013 Jan;34:200-9; Thompson BA et al. Nat. Genet. 2014 Feb;46:107-15; available at [www.insight-group.org/variants/classifications/]). In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was determined to be functionally deleterious (Jia X et al. Am J Hum Genet, 2021 01;108:163-175). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Myriad Genetics, Inc.	RCV004789180	SCV005405662	likely pathogenic	Lynch syndrome 1	2024-09-18	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 33357406]. This variant is expected to disrupt protein structure [Myriad internal data].
Labcorp Genetics (formerly Invitae), Labcorp	RCV005092336	SCV005775722	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-12-29	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 695 of the MSH2 protein (p.Val695Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with endometrial cancer (internal data). ClinVar contains an entry for this variant (Variation ID: 633496). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 33357406) indicates that this missense variant is expected to disrupt MSH2 function with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.