Submissions for variant NM_000179.3(MSH6):c.1474A>G (p.Met492Val)

gnomAD frequency: 0.00008  dbSNP: rs61754783

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000587662	SCV000149283	uncertain significance	not provided	2023-08-28	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate no damaging effect: mismatch repair activity comparable to wild-type (Drost et al., 2012); Identified in individuals with Lynch syndrome-associated and other cancers (Wagner et al., 2003; Nilbert et al., 2009; Okkels et al., 2012; Pal et al., 2012; Shindo et al., 2017; Yehia et al., 2018); This variant is associated with the following publications: (PMID: 23047549, 26333163, 23621914, 12658575, 18566915, 22495361, 28767289, 29684080, 29899834, 31391288, 31422818, 17531815, 21120944, 22102614, 33471991)
Ambry Genetics	RCV000115374	SCV000185429	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-08	criteria provided, single submitter	clinical testing	The p.M492V variant (also known as c.1474A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 1474. The methionine at codon 492 is replaced by valine, an amino acid with highly similar properties. This alteration has been reported as a variant of unknown significance in multiple individuals, including one family from the Danish HNPCC-registry (Nilbert M et al. Fam. Cancer. 2009 Jun;8:75-83), one family meeting Amsterdam criteria (Wagner A et al. Am. J. Hum. Genet. 2003 May;72:1088-100), two unrelated individuals from HNPCC families with colon tumors demonstrating normal MSH6 expression on IHC studies (Okkels H et al. Appl. Immunohistochem. Mol. Morphol. 2012 Oct;20:470-7), and a patient diagnosed with a pancreatic neuroendocrine tumor at age 57 (Shindo K et al. J. Clin. Oncol. 2017 Oct;35:3382-3390). In addition, one functional study reported this variant to be proficient in in vitro mismatch repair (MMR) activity (Drost M et al. Hum. Mutat. 2012 Mar;33:488-94). 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 available evidence, the clinical significance of this alteration remains unclear.
Invitae	RCV000524111	SCV000260884	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-24	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000212649	SCV000712331	uncertain significance	not specified	2016-11-30	criteria provided, single submitter	clinical testing	The p.Met492Val variant in MSH6 has been reported in 4 individuals with Lynch sy ndrome-related cancers (Wagner 2003, Okkels 2012, Pal 2012). In vitro functional studies provide some evidence that the p.Met492Val variant may not impact prote in function (Drost 2012). However, these types of assays may not accurately repr esent biological function. This variant has been identified in 3/6610 Finnish ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs61754783). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In addit ion, this variant was classified as a Variant of Uncertain Significance on Sep 5 , 2013 by the ClinGen-approved InSiGHT expert panel (ClinVar SCV000107859.2). In summary, the clinical significance of the p.Met492Val variant is uncertain.
PreventionGenetics, part of Exact Sciences	RCV000587662	SCV000805844	uncertain significance	not provided	2017-05-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115374	SCV000902794	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-06	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with valine at codon 492 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). A functional study has shown that this variant does not affect MSH6 mismatch repair activity (PMID: 22102614). This variant has been reported in individuals with Lynch syndrome (PMID: 12658575, 18566915, 22495361), in an individual affected with ovarian cancer (PMID: 23047549), and in an individual affected with pancreatic neuroendocrine tumor (PMID: 28767289). This variant occurs at an elevated frequency in the general population and has been identified in 23/282572 chromosomes 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000587662	SCV002010118	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212649	SCV002760660	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587662	SCV002774639	uncertain significance	not provided	2023-05-22	criteria provided, single submitter	clinical testing	In the published literature, this variant has been identified in individuals with Lynch syndrome (PMID: 22495361 (2012), 18566915 (2009), 12658575 (2003)), ovarian cancer (PMID: 23047549 (2012)), and pancreatic cancer (PMID: 28767289 (2017)). In a large-scale breast cancer association study, the variant was observed in individuals with breast cancer as well as unaffected individuals (see LOVD (http://databases.lovd.nl/shared/genes/MSH6) and PMID: 33471991 (2021)). An in vitro functional study has reported that this variant causes a slight reduction in mismatch repair activity (PMID: 22102614 (2012)). The frequency of this variant in the general population, 0.00048 (12/25118 chromosomes in European (Finnish) subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV003997066	SCV004843677	uncertain significance	Lynch syndrome	2023-12-15	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with valine at codon 492 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). A functional study has shown that this variant does not affect MSH6 mismatch repair activity (PMID: 22102614). This variant has been reported in individuals with Lynch syndrome (PMID: 12658575, 18566915, 22495361), in an individual affected with ovarian cancer (PMID: 23047549), and in an individual affected with pancreatic neuroendocrine tumor (PMID: 28767289). This variant occurs at an elevated frequency in the general population and has been identified in 23/282572 chromosomes 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	RCV001353728	SCV000592585	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The p.Met492Val variant was identified in 2 of 2234 proband chromosomes (frequency: 0.001) from families with Lynch syndrome (Nilbert 2009, Wagner 2003); however, control chromosomes were not evaluated in these studies, thus the prevalence of this variant in the general population could not be determined. The variant was also identified in dbSNP (ID: rs61754783) “With Uncertain significance allele”, HGMD, “Mismatch Repair Genes Variant Database”, “InSiGHT Colon Cancer Database”, ClinVar database (classified as having uncertain significance by the InSiGHT expert review panel), and UMD (1X as an unclassified variant). An in vitro functional study by Drost (2011) demonstrated that the variant had similar mismatch repair efficiency to wild type MSH6, and an in silico study analyzing structural properties suggests that the variant has no impact on the MSH6 protein (Terui 2013).The p.Met492 residue is conserved in mammals but not across all lower organisms, 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. 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 unknown significance.