Submissions for variant NM_000179.3(MSH6):c.1729C>G (p.Arg577Gly)

dbSNP: rs542838372

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766399	SCV000279929	uncertain significance	not provided	2023-06-15	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with a personal history of colorectal cancer (Loizidou et al., 2014); This variant is associated with the following publications: (PMID: 30798936, 25133505, 17531815, 21120944, 28195393)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000223441	SCV000601514	uncertain significance	not specified	2016-12-07	criteria provided, single submitter	clinical testing
Invitae	RCV000555846	SCV000624686	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000564916	SCV000662397	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-23	criteria provided, single submitter	clinical testing	The p.R577G variant (also known as c.1729C>G), located in coding exon 4 of the MSH6 gene, results from a C to G substitution at nucleotide position 1729. The arginine at codon 577 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is highly 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.
Color Diagnostics, LLC DBA Color Health	RCV000564916	SCV000685221	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000223441	SCV002074436	uncertain significance	not specified	2022-01-26	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.1729C>G (p.Arg577Gly) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, connector domain of the encoded protein sequence. Three 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 250210 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.1729C>G in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000564916	SCV002535653	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-22	criteria provided, single submitter	curation
Baylor Genetics	RCV003469114	SCV004197606	uncertain significance	Endometrial carcinoma	2023-10-19	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998645	SCV004837784	uncertain significance	Lynch syndrome	2023-05-31	criteria provided, single submitter	clinical testing