Submissions for variant NM_000179.3(MSH6):c.2926C>T (p.Arg976Cys)

gnomAD frequency: 0.00001  dbSNP: rs587782386

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131393	SCV000186369	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-02-15	criteria provided, single submitter	clinical testing	The p.R976C variant (also known as c.2926C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 2926. The arginine at codon 976 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been identified in probands whose Lynch syndrome-associated tumor demonstrated high microsatellite instability and/or loss of MSH6 expression by immunohistochemistry (IHC), as well as probands whose Lynch syndrome-associated tumor was microsatellite stable (MSS) and/or demonstrated normal mismatch repair protein expression by IHC (Ambry internal data). Another alteration at the same codon, p.R976H (c.2927G>A), has been detected in individuals suspected of having Lynch syndrome (Plaschke J et al. Int. J. Cancer. 2002 Feb;97:643-8; Ambry internal data). Based on internal structural analysis, this alteration causes destabilization at the interface between the lever and clamp domains where other pathogenic alterations are present (Warren JJ et al. Mol. Cell. 2007 May;26:579-92). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx	RCV000212673	SCV000211304	uncertain significance	not provided	2022-05-19	criteria provided, single submitter	clinical testing	Observed in a patient with endometrial cancer and tumor studies consistent with pathogenic variants in this gene (Gray 2018); 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: 25980754, 30702970, 29755653, 11807791, 23621914)
Invitae	RCV000630013	SCV000750969	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-10-03	criteria provided, single submitter	clinical testing	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. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MSH6 protein function. ClinVar contains an entry for this variant (Variation ID: 142327). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 25980754, 30702970). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 976 of the MSH6 protein (p.Arg976Cys).
Genetic Services Laboratory, University of Chicago	RCV001818325	SCV002064698	uncertain significance	not specified	2019-07-26	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003462013	SCV004195554	uncertain significance	Endometrial carcinoma	2023-08-25	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998102	SCV004839000	uncertain significance	Lynch syndrome	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 976 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with or suspected of having Lynch syndrome (PMID: 25980754, 29755653, 30702970, 31391288). 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355155	SCV001549949	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH6 p.Arg976Cys variant was identified in 1 of 2520 proband chromosomes (frequency: 0.0004) from individuals or families who had a history of Lynch syndrome-associated cancer and/or polyps, the affected individual also carrying other variants: NBN c.1489A>G, p.Thr497Ala, PTEN c.802-51_802-14del, and monoallelic MUTYH c.1227_1228dupGG (p.Glu410Glyfs*43) (Yurgelun_2015_25980754). The variant was also identified in dbSNP (ID: rs587782386) “With Likely pathogenic allele”, ClinVar (classified with conflicting interpretations of pathogenicity; likely pathogenic by Ambry Genetics and uncertain significance by GeneDx), and Clinvitae (2x). The variant was not identified in Cosmic, MutDB, UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. The p.Arg976 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.