Submissions for variant NM_000179.3(MSH6):c.3493T>C (p.Cys1165Arg)

dbSNP: rs1669872142

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001325048	SCV001516021	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2020-10-08	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine with arginine at codon 1165 of the MSH6 protein (p.Cys1165Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH6-related conditions. 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.
Ambry Genetics	RCV002456451	SCV002615798	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-30	criteria provided, single submitter	clinical testing	The p.C1165R variant (also known as c.3493T>C), located in coding exon 6 of the MSH6 gene, results from a T to C substitution at nucleotide position 3493. The cysteine at codon 1165 is replaced by arginine, an amino acid with highly dissimilar properties. This alteration has been reported as functionally defective based on results from a complementation assay performed in mammalian cells (Drost M et al. Genet. Med., 2020 May;22:847-856). In addition, this alteration has been observed in at least one individual with a personal and/or family history that is consistent with Lynch syndrome (Ambry internal data). 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.
Myriad Genetics, Inc.	RCV003449934	SCV004189264	likely pathogenic	Lynch syndrome 5	2023-08-24	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 31965077]. This variant is expected to disrupt protein structure [Myriad internal data].