ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.1070A>T (p.Glu357Val)

dbSNP: rs150503781
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001953959 SCV002246656 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2021-04-19 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with valine at codon 357 of the MSH2 protein (p.Glu357Val). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH2-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MSH2 protein function. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV004999577 SCV005623604 uncertain significance not provided 2023-10-20 criteria provided, single submitter clinical testing The MSH2 c.1070A>T (p.Glu357Val) variant, to the best of our knowledge, has not been reported in individuals with MSH2-related conditions in the published literature. A screening assay based on cell survival in response to 6-thioguanine treatment indicates this and most of the other missense variants at this codon have neutral effects on DNA mismatch repair function (PMID: 33357406 (2021)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.

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