Submissions for variant NM_000179.3(MSH6):c.2282G>C (p.Arg761Thr)

dbSNP: rs587779233

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000793348	SCV000932696	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-06-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001190571	SCV001358085	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-04	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with threonine at codon 761 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MSH6-related disorders in the literature. This variant has been identified in 2/251122 chromosomes 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193700	SCV001362733	uncertain significance	not specified	2019-04-03	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.2282G>C (p.Arg761Thr) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 245860 control chromosomes (gnomAD). 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.2282G>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 to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Division of Medical Genetics, University of Washington	RCV001257482	SCV001434288	uncertain significance	Lynch syndrome 5	2020-04-01	criteria provided, single submitter	clinical testing	To our knowledge, this sequence variant has not been previously reported in the literature. This variant has an overall allele frequency of 0.000008 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate that this variant may not alter protein structure/function. Thus, it is unknown at this time whether this variant increases cancer risk. PM2; BP4
Ambry Genetics	RCV001190571	SCV002734700	uncertain significance	Hereditary cancer-predisposing syndrome	2024-06-10	criteria provided, single submitter	clinical testing	The p.R761T variant (also known as c.2282G>C), located in coding exon 4 of the MSH6 gene, results from a G to C substitution at nucleotide position 2282. The arginine at codon 761 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV003314645	SCV004014548	uncertain significance	not provided	2023-01-17	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 17531815, 21120944)