Submissions for variant NM_000179.3(MSH6):c.1573A>G (p.Ser525Gly)

dbSNP: rs1572723488

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001012212	SCV001172638	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-29	criteria provided, single submitter	clinical testing	The p.S525G variant (also known as c.1573A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 1573. The serine at codon 525 is replaced by glycine, an amino acid with similar properties. This alteration was identified in a cohort of 1644 colorectal cancer patients (Baert-Desurmont S et al. Eur. J. Hum. Genet., 2018 11;26:1597-1602). 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	RCV001247613	SCV001421046	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-17	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 525 of the MSH6 protein (p.Ser525Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 819559). 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 MSH6 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.
Color Diagnostics, LLC DBA Color Health	RCV001012212	SCV002052670	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-20	criteria provided, single submitter	clinical testing	This missense variant replaces serine with glycine at codon 525 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer 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	RCV003339424	SCV004047508	uncertain significance	Lynch syndrome 5		criteria provided, single submitter	clinical testing	The missense variant c.1573A>G (p.Ser525Gly) in MSH6 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Ser525Gly variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Uncertain Significance. The amino acid Ser at position 525 is changed to a Gly changing protein sequence and it might alter its composition and physico-chemical properties.The amino acid change p.Ser525Gly in MSH6 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance (VUS).
All of Us Research Program, National Institutes of Health	RCV004004509	SCV004839495	uncertain significance	Lynch syndrome	2023-11-09	criteria provided, single submitter	clinical testing	This missense variant replaces serine with glycine at codon 525 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer 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.