Submissions for variant NM_000251.3(MSH2):c.247A>G (p.Met83Val)

dbSNP: rs766196837

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000460763	SCV000548288	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-09-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000523794	SCV000618248	uncertain significance	not provided	2016-11-10	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.247A>G at the cDNA level, p.Met83Val (M83V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Met83Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Methionine and Valine share similar properties, this is considered a conservative amino acid substitution. MSH2 Met83Val occurs at a position where amino acids with properties similar to Methionine are tolerated across species and is located in the mismatch binding domain (Lützen 2008, Kansikas 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Met83Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000575381	SCV000669860	likely benign	Hereditary cancer-predisposing syndrome	2023-09-20	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.
Color Diagnostics, LLC DBA Color Health	RCV000575381	SCV000690076	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-19	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with valine at codon 83 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 been observed in an individual affected with colorectal cancer (PMID: 28135145). This variant has not been identified 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.
GeneKor MSA	RCV000575381	SCV000822052	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004000791	SCV004832105	uncertain significance	Lynch syndrome	2023-02-15	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with valine at codon 83 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 been observed in an individual affected with colorectal cancer (PMID: 28135145). This variant has not been identified 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.