Submissions for variant NM_000179.3(MSH6):c.3220A>G (p.Met1074Val)

dbSNP: rs730881804

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000587626	SCV000211315	uncertain significance	not provided	2018-08-14	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.3220A>G at the cDNA level, p.Met1074Val (M1074V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). This variant has been observed in an individual with suspected Hereditary Nonpolyposis Colorectal Cancer whose tumor demonstrated decreased, but not absent, MSH6 expression on immunohistochemistry (Okkels 2012). MSH6 Met1074Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the lever domain (Warren 2007, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH6 Met1074Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000232219	SCV000283792	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-11-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000562784	SCV000662419	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-26	criteria provided, single submitter	clinical testing	The p.M1074V variant (also known as c.3220A>G), located in coding exon 5 of the MSH6 gene, results from an A to G substitution at nucleotide position 3220. The methionine at codon 1074 is replaced by valine, an amino acid with highly similar properties. This alteration has been identified in one individual with colorectal cancer demonstrating decreased MSH6 staining via immunohistochemistry; however, detailed personal and family history was not provided (Okkels H et al. Appl Immunohistochem Mol Morphol, 2012 Oct;20:470-7). This alteration has also been reported in 1/60466 breast cancer cases and in 1/53461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000562784	SCV000690331	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-03	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with valine at codon 1074 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual suspected being affected with Lynch syndrome (PMID: 22495361). This variant has been identified in 1/251360 chromosomes 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488409	SCV000695844	uncertain significance	not specified	2023-12-01	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3220A>G (p.Met1074Val) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, core (IPR007696) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251360 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3220A>G has been reported in the literature in at least one individual with a colon adenocarcinoma and suspected HNPCC, however, this report does not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer (Okkels_2012). One publication reports experimental evidence evaluating an impact on protein function, demonstrating that the variant causes reduced MSH6 expression via immunohistrochemistry (Okkels_2012). However, this does not allow convincing conclusions about the variant effect. The following publication have been ascertained in the context of this evaluation (PMID: 22495361). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014; four submitters cliassified the variant as uncertain significance, while one submitter classified it as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000562784	SCV002527985	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-14	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV003998502	SCV004835006	uncertain significance	Lynch syndrome	2023-09-17	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with valine at codon 1074 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual suspected being affected with Lynch syndrome (PMID: 22495361). This variant has been identified in 1/251360 chromosomes 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.