Submissions for variant NM_000251.3(MSH2):c.1013G>T (p.Gly338Val)

dbSNP: rs587779065

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000689433	SCV000817084	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2018-04-30	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with MSH2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with valine at codon 338 of the MSH2 protein (p.Gly338Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV001269518	SCV001449558	likely pathogenic	not provided	2015-04-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002352132	SCV002622502	pathogenic	Hereditary cancer-predisposing syndrome	2021-08-05	criteria provided, single submitter	clinical testing	The p.G338V pathogenic mutation (also known as c.1013G>T), located in coding exon 6 of the MSH2 gene, results from a G to T substitution at nucleotide position 1013. The glycine at codon 338 is replaced by valine, an amino acid with dissimilar properties. 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). In another functional study that measured the mutation rate of MSH2 alterations in yeast, this alteration demonstrated a 7.98-fold increase in mutation rate compared to MSH2 wild-type, which was considered potentially pathogenic (Ollodart AR et al. Genetics, 2021 Jun;218:iyab058). Based on internal structural analysis using published crystal structures, G338V is strongly destabilizing to the MSH2 MutS domain III (Warren JJ et al. Mol Cell, 2007 May;26:579-92; Ambry internal data). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV003453433	SCV004186673	likely pathogenic	Lynch syndrome 1	2023-07-31	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].