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

dbSNP: rs1553412195

Total submissions: 5

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
Invitae	RCV000705703	SCV000834714	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-16	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 Lynch syndrome along with a MLH1 c.1989G>A splice variant (PMID: 27601186). 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	2022-01-07	criteria provided, single submitter	clinical testing	The c.773T>C (p.I258T) alteration is located in exon 4 (coding exon 4) of the MSH6 gene. This alteration results from a T to C substitution at nucleotide position 773, causing the isoleucine (I) at amino acid position 258 to be replaced by a threonine (T). Based on insufficient or conflicting 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