Submissions for variant NM_000179.3(MSH6):c.2108T>C (p.Met703Thr)

dbSNP: rs1064793189

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000486361	SCV000565223	uncertain significance	not provided	2016-04-21	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.2108T>C at the cDNA level, p.Met703Thr (M703T) at the protein level, and results in the change of a Methionine to a Threonine (ATG>ACG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Met703Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Methionine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Met703Thr occurs at a position that is not conserved and is located within domain II of the MutS domain (Terui 2013). 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 Met703Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000563641	SCV000669918	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-10	criteria provided, single submitter	clinical testing	The p.M703T variant (also known as c.2108T>C), located in coding exon 4 of the MSH6 gene, results from a T to C substitution at nucleotide position 2108. The methionine at codon 703 is replaced by threonine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000703273	SCV000832168	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-09-25	criteria provided, single submitter	clinical testing	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: 418326). 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) performed at Invitae indicates that this missense variant is not expected to disrupt 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. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 703 of the MSH6 protein (p.Met703Thr).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193732	SCV001362791	uncertain significance	not specified	2019-10-03	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.2108T>C (p.Met703Thr) results in a non-conservative amino acid change in 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 250756 control chromosomes. 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.2108T>C in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355364	SCV001550234	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The p.Met703Thr variant was not identified in the literature, nor was it identified in dbSNP NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC) database, HGMD, Clinvitae database, COSMIC, “Mismatch Repair Genes Variant Database”, “MMR Gene Unclassified Variants Database”, InSiGHT Colon Cancer Gene Variant Database, “Zhejiang Colon Cancer Database”, the ClinVar database , GeneInsight COGR database, or UMD. The p.Met703 residue is conserved across mammals and other organisms, the exception being chicken, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Threonine (Thr) variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. The identification of this variant as co-occurring with a pathogenic variant in one individual from our laboratory, increases the likelihood this variant may not have clinical significance. 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 (VUS).
PreventionGenetics, part of Exact Sciences	RCV004740253	SCV005367087	uncertain significance	MSH6-related disorder	2024-05-02	no assertion criteria provided	clinical testing	The MSH6 c.2108T>C variant is predicted to result in the amino acid substitution p.Met703Thr. To our knowledge, this variant has not been reported in the literature or in gnomAD, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.