Submissions for variant NM_000179.3(MSH6):c.1093T>C (p.Trp365Arg)

dbSNP: rs752628520

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
University of Washington Department of Laboratory Medicine, University of Washington	RCV000758607	SCV000887362	uncertain significance	Lynch syndrome	2018-05-01	criteria provided, single submitter	clinical testing	MSH6 NM_000179.2:c.1093T>C has a 59.6% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 0.16 to 1, generated from evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at the MSH6 locus. See Shirts et al 2018, PMID 29887214.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001526921	SCV001737680	uncertain significance	not specified	2021-06-14	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.1093T>C (p.Trp365Arg) 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 allele was found at a frequency of 4e-06 in 251092 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.1093T>C in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant in the somatic state to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae	RCV001855908	SCV002159534	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2021-02-05	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 619535). This variant is present in population databases (rs752628520, ExAC 0.001%). This sequence change replaces tryptophan with arginine at codon 365 of the MSH6 protein (p.Trp365Arg). The tryptophan residue is moderately conserved and there is a moderate physicochemical difference between tryptophan and arginine. 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 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.