Submissions for variant NM_000179.3(MSH6):c.3416G>A (p.Gly1139Asp)

dbSNP: rs1316409501

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000704717	SCV000833676	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-08-22	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1139 of the MSH6 protein (p.Gly1139Asp). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with MSH6-related conditions (PMID: 34897210). ClinVar contains an entry for this variant (Variation ID: 581014). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 31965077). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (PMID: 32123317). 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	RCV001524596	SCV001734517	uncertain significance	Hereditary cancer-predisposing syndrome	2020-11-03	criteria provided, single submitter	clinical testing	This missense variant replaces a conserved glycine with aspartic acid at codon 1139 in the ATPase domain (the Walker A motif) of the MSH6 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). Functional studies have shown that this variant protein and its equivalent in the mouse and budding yeast MSH6 homologs are defective in DNA mismatch repair and associated activities (PMID: 9819445, 31965077). To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. However, a different missense variant p.Gly1139Ser has been observed in at least two individuals affected with Lynch syndrome (PMID: 16203774, 18301448) and found to be defective in DNA mismatch repair and related functional assays (PMID: 22102614, 24040339, 28531214, 31965077). This variant has been identified in 1/251346 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV001524596	SCV002618551	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-05-27	criteria provided, single submitter	clinical testing	The p.G1139D variant (also known as c.3416G>A), located in coding exon 5 of the MSH6 gene, results from a G to A substitution at nucleotide position 3416. The glycine at codon 1139 is replaced by aspartic acid, an amino acid with similar properties. This variant has been identified in a proband whose Lynch syndrome-associated tumor demonstrated loss of MSH6 expression by immunohistochemistry (Ambry internal data). Another variant at the same codon, p.G1139S (c.3415G>A), demonstrated deficient mismatch repair activity in functional studies and was detected in individuals with MSI-H colorectal tumors that showed loss of MSH2 and/or MSH6 expression by immunohistochemistry (Drost M et al. Hum Mutat, 2012 Mar;33:488-94; Wielders EA et al. PLoS One, 2013 Sep;8:e74766; Houlleberghs H et al. PLoS Genet, 2017 May;13:e1006765; Drost M et al. Genet Med, 2020 05;22:847-856; 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). Based on internal structural analysis, G1139D 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 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.	RCV003453499	SCV004185559	likely pathogenic	Lynch syndrome 5	2023-08-23	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 31965077]. This variant is expected to disrupt protein structure [Myriad internal data].
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV003453499	SCV004807259	uncertain significance	Lynch syndrome 5	2024-03-26	criteria provided, single submitter	clinical testing
GeneDx	RCV004721570	SCV005326749	likely pathogenic	not provided	2023-09-14	criteria provided, single submitter	clinical testing	Published functional studies demonstrate reduced mismatch repair (MMR) activity (Drost et al., 2020); 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: 37076482, 32123317, 31965077, 21120944, 12019211, 17531815)