Submissions for variant NM_000179.3(MSH6):c.3410T>C (p.Met1137Thr)

dbSNP: rs1553331742

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000629949	SCV000750905	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-03-01	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1137 of the MSH6 protein (p.Met1137Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 525720). 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. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193729	SCV001362787	uncertain significance	not specified	2019-06-25	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3410T>C (p.Met1137Thr) results in a non-conservative amino acid change located in the C-terminal (IPR000432) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251346 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3410T>C in individuals affected with Hereditary Non-Polyposis Colon Cancer and no experimental evidence demonstrating its impact on protein function have been reported. However, an internal sample reports the variant to co-occur with a likely pathogenic MSH6 variant, c.3416dupG, therefore, supporting a possible benign role. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS - possibly benign.
Ambry Genetics	RCV002457986	SCV002612752	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-06	criteria provided, single submitter	clinical testing	The p.M1137T variant (also known as c.3410T>C), located in coding exon 5 of the MSH6 gene, results from a T to C substitution at nucleotide position 3410. The methionine at codon 1137 is replaced by threonine, an amino acid with similar properties. 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.
GeneDx	RCV003238789	SCV003936390	uncertain significance	not provided	2023-06-27	criteria provided, single submitter	clinical testing	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; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 12019211, 17531815, 21120944)
Color Diagnostics, LLC DBA Color Health	RCV002457986	SCV004357719	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-01	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with threonine at codon 1137 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 not been reported in individuals affected with MSH6-related disorders in the literature. 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.
All of Us Research Program, National Institutes of Health	RCV004002785	SCV004835065	uncertain significance	Lynch syndrome	2023-06-26	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with threonine at codon 1137 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 not been reported in individuals affected with MSH6-related disorders in the literature. 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.