Submissions for variant NM_000179.3(MSH6):c.1180T>G (p.Ser394Ala)

dbSNP: rs1553412587

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001321131	SCV001511949	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-31	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 394 of the MSH6 protein (p.Ser394Ala). 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: 433908). 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%. Experimental studies have shown that this missense change does not substantially affect MSH6 function (PMID: 31965077). 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.
Ambry Genetics	RCV002341183	SCV002635336	uncertain significance	Hereditary cancer-predisposing syndrome	2024-05-03	criteria provided, single submitter	clinical testing	The p.S394A variant (also known as c.1180T>G), located in coding exon 4 of the MSH6 gene, results from a T to G substitution at nucleotide position 1180. The serine at codon 394 is replaced by alanine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000501660	SCV000592580	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The p.Ser394Ala variant has not been previously reported in the literature. This residue is not conserved in mammals and computational analyses (PolyPhen, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. The identification of this variant in the present of a second pathogenic variant increases the likelihood that this variant does not have clinical significance. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as predicted benign.