Submissions for variant NM_000179.3(MSH6):c.3467T>C (p.Met1156Thr)

dbSNP: rs876659549

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000217088	SCV000276138	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-21	criteria provided, single submitter	clinical testing	The p.M1156T variant (also known as c.3467T>C), located in coding exon 6 of the MSH6 gene, results from a T to C substitution at nucleotide position 3467. The methionine at codon 1156 is replaced by threonine, an amino acid with similar properties. This variant was identified once in a study where patients underwent NGS panel testing for the mismatch repair and familial adenomatous polyposis genes (Rey JM et al. J Mol Diagn, 2017 07;19:589-601). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000475398	SCV000551196	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-26	criteria provided, single submitter	clinical testing
GeneDx	RCV000482975	SCV000568007	uncertain significance	not provided	2017-07-05	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.3467T>C at the cDNA level, p.Met1156Thr (M1156T) at the protein level, and results in the change of a Methionine to a Threonine (ATG>ACG). This variant was observed in a patient that underwent testing for hereditary colon cancer (Rey 2017). MSH6 Met1156Thr was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Methionine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Met1156Thr occurs at a position where amino acids with properties similar to Methionine are tolerated across species and is located within the ATPase domain (Warren 2007, Kansikas 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Met1156Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000217088	SCV000690358	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-17	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with threonine at codon 1156 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a cohort of individuals undergoing mismatch repair and familial adenomatous polyposis gene testing (PMID: 28502729). This variant has been identified in 1/251398 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.
Counsyl	RCV000662884	SCV000785793	uncertain significance	Lynch syndrome 5	2017-11-28	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000662884	SCV004018436	uncertain significance	Lynch syndrome 5	2023-03-27	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.
All of Us Research Program, National Institutes of Health	RCV003997945	SCV004835075	uncertain significance	Lynch syndrome	2023-04-03	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with threonine at codon 1156 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a cohort of individuals undergoing mismatch repair and familial adenomatous polyposis gene testing (PMID: 28502729). This variant has been identified in 1/251398 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.