Submissions for variant NM_000251.3(MSH2):c.908A>G (p.Asp303Gly)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
All of Us Research Program, National Institutes of Health	RCV004015469	SCV004842540	uncertain significance	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 303 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. 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.
Neuberg Centre For Genomic Medicine, NCGM	RCV004555712	SCV005044782	uncertain significance	Lynch syndrome 1		criteria provided, single submitter	clinical testing	The missense c.908A>Gp.Asp303Gly variant in MSH2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is novel not in any individuals in gnomAD Exomes and 1000 Genomes. The amino acid Asp at position 303 is changed to a Gly changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Asp303Gly in MSH2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The variant is predicted as damaging by SIFT. For these reasons, this variant has been classified as Uncertain Significance.