Submissions for variant NM_000251.3(MSH2):c.199A>G (p.Met67Val)

gnomAD frequency: 0.00001  dbSNP: rs768824654

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000195508	SCV000254397	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-09-17	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 67 of the MSH2 protein (p.Met67Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 216347). Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is not expected to disrupt MSH2 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Color Diagnostics, LLC DBA Color Health	RCV000581797	SCV000690035	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-05	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with valine at codon 67 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). To our knowledge, this variant has not been reported in individuals affected with MSH2-related disorders in the literature. 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.
GeneDx	RCV001770148	SCV002001210	uncertain significance	not provided	2020-11-27	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); While protein-based in silico analysis supports that this missense variant does not alter protein structure/function, splice predictors support a deleterious effect. In the absence of RNA or functional studies, the actual effect of this sequence change is unknown.; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV000581797	SCV002721783	likely benign	Hereditary cancer-predisposing syndrome	2021-03-29	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003114359	SCV003800690	uncertain significance	not specified	2023-01-19	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.199A>G (p.Met67Val) results in a conservative amino acid change located in the DNA mismatch repair protein MutS-like, N-terminal domain (IPR007695) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-06 in 228538 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.199A>G in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and one ClinVar submitter (evaluation after 2014) cites it as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV003997016	SCV004832038	uncertain significance	Lynch syndrome	2023-10-23	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with valine at codon 67 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). To our knowledge, this variant has not been reported in individuals affected with MSH2-related disorders in the literature. 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.