Submissions for variant NM_000179.3(MSH6):c.3722G>A (p.Cys1241Tyr)

dbSNP: rs1021631442

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000491034	SCV000580239	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-02-15	criteria provided, single submitter	clinical testing	The p.C1241Y variant (also known as c.3722G>A), located in coding exon 8 of the MSH6 gene, results from a G to A substitution at nucleotide position 3722. The cysteine at codon 1241 is replaced by tyrosine, an amino acid with highly dissimilar properties. In one study, this alteration was detected in 1/1893 individuals with epithelial ovarian cancer and was predicted to be pathogenic based on in silico prediction models (Pal T et al. Br. J. Cancer 2012 Nov; 107(10):1783-90). This alteration has been observed in at least one individual with a personal and/or family history that is consistent with MSH6-related disease (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000664316	SCV000788252	likely pathogenic	Lynch syndrome	2018-02-07	criteria provided, single submitter	clinical testing	The MSH6 p.C1241Y variant has has been reported once in a woman with ovarian cancer (Pal 2012). The variant occurs at a position that is evolutionarily conserved. Testing performed on tumor tissue of a patient with constitutional MSH6 p.C1241Y variant supports that this variant is likely pathogenic. Specifically, in the patient's tumor the constitutional MSH6 variant was seen with a single somatic mutation at heterozygous freqency in MSH6 in the tumor, without evidence of loss of heterozygosity at MSH6 .
Invitae	RCV002523440	SCV003524643	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-09-19	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 1241 of the MSH6 protein (p.Cys1241Tyr). 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: 23047549, 30877237). ClinVar contains an entry for this variant (Variation ID: 428361). 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.