Submissions for variant NM_000179.3(MSH6):c.3604A>G (p.Met1202Val)

gnomAD frequency: 0.00001  dbSNP: rs369778514

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129582	SCV000184364	uncertain significance	Hereditary cancer-predisposing syndrome	2022-04-07	criteria provided, single submitter	clinical testing	The p.M1202V variant (also known as c.3604A>G), located in coding exon 7 of the MSH6 gene, results from an A to G substitution at nucleotide position 3604. The methionine at codon 1202 is replaced by valine, an amino acid with highly similar properties. This amino acid position is poorly 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.
Counsyl	RCV000411815	SCV000488741	uncertain significance	Lynch syndrome 5	2016-06-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000479516	SCV000565928	uncertain significance	not provided	2017-12-01	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.3604A>G at the cDNA level, p.Met1202Val (M1202V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Met1202Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Methionine and Valine share similar properties, this is considered a conservative amino acid substitution. MSH6 Met1202Val is located within the ATPase domain (Warren 2007, Kansikas 2011). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH6 Met1202Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000129582	SCV000685419	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-26	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with valine at codon 1202 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/251442 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	RCV000780465	SCV000917737	uncertain significance	not specified	2017-10-20	criteria provided, single submitter	clinical testing	Variant summary: The c.3604A>G (p.Met1202Val) variant in the MSH6 gene is a missense variant that involves a mildly conserved nucleotide and 5/5 in silico tools predict benign outcome, however no functional studies supporting these predictions were published at the time of evaluation. The c.3604A>G is present in the control population datasets of ExAC and gnomAD at a low frequency (1/121324 and 2/246248 chrs tested, respectively). The observed frequency does not exceed the maximum expected allele frequency for a pathogenic variant of 0.0001, suggesting that it is not a common polymorphism. To our knowledge, the variant has not been reported in affected individuals via peer-reviewed reports, but is cited as VUS by reputable databases/clinical laboratories. Taken together, the variant was classified as VUS, until new information becomes available.
Invitae	RCV000810760	SCV000950993	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000411815	SCV004019053	uncertain significance	Lynch syndrome 5	2023-03-29	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV003460896	SCV004195725	uncertain significance	Endometrial carcinoma	2023-06-16	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997512	SCV004835101	uncertain significance	Lynch syndrome	2023-10-30	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with valine at codon 1202 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/251442 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.