Submissions for variant NM_000179.3(MSH6):c.3415G>A (p.Gly1139Ser)

dbSNP: rs63751063

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002452190	SCV002616535	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-04-20	criteria provided, single submitter	clinical testing	The p.G1139S variant (also known as c.3415G>A), located in coding exon 5 of the MSH6 gene, results from a G to A substitution at nucleotide position 3415. The glycine at codon 1139 is replaced by serine, an amino acid with similar properties. This alteration has been identified in individuals whose colorectal tumors demonstrated high microsatellite instability with loss of MSH2 and/or MSH6 staining on immunohistochemistry (Woods MO et al. Clin Cancer Res, 2005 Oct;11:6853-61; Steinke V et al. Eur J Hum Genet, 2008 May;16:587-92). In complementation studies performed in vitro, G1139S demonstrated deficient mismatch repair (MMR) activity (Drost M et al. Hum Mutat, 2012 Mar;33:488-94; Drost M et al. Genet Med, 2020 05;22:847-856). In additional functional studies, G1139S showed reduced protein expression when compared to wild type MSH6 and MMR activity was abrogated in the presence of DNA damaging agents (Wielders EA et al. PLoS One, 2013 Sep;8:e74766; Houlleberghs H et al. PLoS Genet, 2017 May;13:e1006765). In another report, GFP-tagged MSH6 G1139S showed nuclear localization when transiently expressed in MMR proficient mammalian cells similar to wild type MSH6 (Belvederesi L et al. Fam Cancer, 2012 Dec;11:675-80). Based on internal structural analysis, G1139S disrupts a key position in the MSH6 phosphate-binding motif (Walker JE et al. EMBO J, 1982;1:945-51; Antony E et al. DNA Repair (Amst), 2006 Feb;5:153-62; 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 majority of available evidence to date, this variant is likely to be pathogenic.
Myriad Genetics, Inc.	RCV003454113	SCV004189256	likely pathogenic	Lynch syndrome 5	2023-08-24	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 22102614, 28531214, 31965077]. This variant is expected to disrupt protein structure [Myriad internal data].
Labcorp Genetics (formerly Invitae), Labcorp	RCV005096266	SCV005834016	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-03-12	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1139 of the MSH6 protein (p.Gly1139Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with colorectal cancer (PMID: 16203774). ClinVar contains an entry for this variant (Variation ID: 1731205). 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 expected to disrupt MSH6 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MSH6 function (PMID: 24040339, 28531214, 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.
GeneDx	RCV005227588	SCV005870234	likely pathogenic	not provided	2024-08-20	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: aberrant resistance to thiopurine 6-thioguanine (6TG) and methylnitronitrosoguanidine (MNNG) and deficient mismatch repair (MMR) activity (PMID: 22102614, 24040339, 28531214, 31965077); Observed in individuals with colorectal cancer, with tumor studies showing loss of MSH6 protein expression on immunohistochemistry (IHC) and/or high microsatellite instability (PMID: 18301448, 16203774, 22851212); 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; This variant is associated with the following publications: (PMID: 16203774, 32615015, 34445333, 22102614, 24040339, 28531214, 22851212, 17531815, 21120944, 12019211, 31965077, 18301448)