Submissions for variant NM_000179.3(MSH6):c.2329T>A (p.Trp777Arg)

dbSNP: rs267608067

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130193	SCV000185030	uncertain significance	Hereditary cancer-predisposing syndrome	2016-10-11	criteria provided, single submitter	clinical testing	The p.W777R variant (also known as c.2329T>A), located in coding exon 4 of the MSH6 gene, results from a T to A substitution at nucleotide position 2329. The tryptophan at codon 777 is replaced by arginine, an amino acid with dissimilar properties. This alteration is reported in the literature in an individual with a MSI high, MLH1 IHC positive, MSH2 IHC negative tumor at age 35 (Steinke V et al. Eur. J. Hum. Genet. 2008; 16:587-92). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 150000 alleles tested) in our clinical cohort. This amino acid position is highly conserved on sequence alignment. This alteration is predicted to be probably damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. In addition, the CoDP in silico tool predicts this alteration will likely impair molecular function, with a score of 0.994 (Terui H et al. J. Biomed. Sci. 2013;20:25).Since supporting evidence is limited at this time, the clinical significance of p.W777R remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000130193	SCV000908397	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-24	criteria provided, single submitter	clinical testing	This missense variant replaces tryptophan with arginine at codon 777 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with early onset colorectal cancer with a tumor demonstrating high microsatellite instability (PMID: 18301448). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
All of Us Research Program, National Institutes of Health	RCV003997074	SCV004842083	uncertain significance	Lynch syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces tryptophan with arginine at codon 777 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with early onset colorectal cancer with a tumor demonstrating high microsatellite instability (PMID: 18301448). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.