Submissions for variant NM_000251.3(MSH2):c.1523G>C (p.Gly508Ala)

dbSNP: rs786202710

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165658	SCV000216395	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-31	criteria provided, single submitter	clinical testing	The p.G508A variant (also known as c.1523G>C), located in coding exon 10 of the MSH2 gene, results from a G to C substitution at nucleotide position 1523. The glycine at codon 508 is replaced by alanine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000688876	SCV000816503	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 508 of the MSH2 protein (p.Gly508Ala). This variant is not present in population databases (gnomAD no frequency). 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: 186123). 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 not expected to disrupt MSH2 protein function with a negative predictive value of 95%. 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.
GeneDx	RCV001560128	SCV001782475	uncertain significance	not provided	2023-07-31	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 9774676, 18822302, 21120944)
All of Us Research Program, National Institutes of Health	RCV003995443	SCV004833507	uncertain significance	Lynch syndrome	2023-05-16	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with alanine at codon 508 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.