ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1729C>G (p.Arg577Gly) (rs542838372)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766399 SCV000279929 uncertain significance not provided 2016-02-29 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1729C>G at the cDNA level, p.Arg577Gly (R577G) at the protein level, and results in the change of an Arginine to a Glycine (CGC>GGC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Arg577Gly was observed with an allele frequency of 0.1% (1/5008) in the American population in 1000 Genomes. Since Arginine and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Arg577Gly occurs at a position that is conserved across species and is located within the MutS Domain II (Terui 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Arg577Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
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 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 577 of the MSH6 protein (p.Arg577Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is present in population databases (rs542838372, ExAC 0.009%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 234864). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV000564916 SCV000662397 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000564916 SCV000685221 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-03 criteria provided, single submitter clinical testing

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