Submissions for variant NM_000179.3(MSH6):c.773T>C (p.Ile258Thr)

dbSNP: rs1553412195

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000584543	SCV000690478	uncertain significance	Hereditary cancer-predisposing syndrome	2019-06-21	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000705703	SCV000834714	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-07-23	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 258 of the MSH6 protein (p.Ile258Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 34897210). ClinVar contains an entry for this variant (Variation ID: 491992). 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 with a negative predictive value of 95%. 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.
Ambry Genetics	RCV000584543	SCV001189218	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-27	criteria provided, single submitter	clinical testing	The p.I258T variant (also known as c.773T>C), located in coding exon 4 of the MSH6 gene, results from a T to C substitution at nucleotide position 773. The isoleucine at codon 258 is replaced by threonine, an amino acid with similar properties. This variant has been identified in conjunction with MLH1 c.1989G>A in a cohort of Swedish families with features consistent with Lynch syndrome (Lagerstedt-Robinson K et al. Oncol. Rep., 2016 Nov;36:2823-2835). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174609	SCV001337806	uncertain significance	not specified	2020-01-13	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.773T>C (p.Ile258Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251164 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.773T>C has been reported in the literature in individuals affected with Lynch Syndrome or FAP (Lagerstedt-Robinson_2016, Kim_2019). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrences with a pathogenic variant has been reported (MLH1 c.1989G>A; Lagerstedt-Robinson_2016), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV004002357	SCV004837019	uncertain significance	Lynch syndrome	2023-04-27	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001174609	SCV005090474	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Molecular Diagnostics Laboratory, Catalan Institute of Oncology	RCV000584543	SCV005901650	uncertain significance	Hereditary cancer-predisposing syndrome	2025-02-23	criteria provided, single submitter	clinical testing	PM2_supporting, BP4 c.773T>C, located in exon 4 of the MSH6 gene, is predicted to result in the substitution of Isoleucine by Threonine at codon 258, p.(Ile258Thr). It is not present in the population database gnomAD v2.1.1, non cancer dataset (PM2_supporting). Computational tools for this variant suggests no significant impact on splicing and does not affect the protein function (MAPP+PolyPhen-2 prior probability for pathogenicity: 0.00) (BP4). To our knowledge, functional studies have been reported for this variant. Co-occurrences with a pathogenic variant has been reported (MLH1 c.1989G>A; Lagerstedt-Robinson 2016). MSH6 c.773T>C has also been reported in a FAP individual (Kim 2019). It has been reported as an uncertain significance in ClinVar. Based on the currently available information, c.773T>C is classified as an uncertain significance variant according to MMR specif. draft v3.1.