ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.1559G>A (p.Gly520Asp)

dbSNP: rs1669344619
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001223696 SCV001395855 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-07-08 criteria provided, single submitter clinical testing This variant has not been reported in the literature in individuals with MSH6-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with aspartic acid at codon 520 of the MSH6 protein (p.Gly520Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15").
Ambry Genetics RCV002402694 SCV002704405 uncertain significance Hereditary cancer-predisposing syndrome 2022-05-09 criteria provided, single submitter clinical testing The p.G520D variant (also known as c.1559G>A), located in coding exon 4 of the MSH6 gene, results from a G to A substitution at nucleotide position 1559. The glycine at codon 520 is replaced by aspartic acid, an amino acid with similar properties. This variant demonstrated reduced mismatch repair activity in vitro and was determined to be functionally deficient (Drost M et al. Genet Med, 2020 05;22:847-856). 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.
Myriad Genetics, Inc. RCV003449707 SCV004189312 likely pathogenic Lynch syndrome 5 2023-08-14 criteria provided, single submitter clinical testing This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 31965077]. This variant is expected to disrupt protein structure [Myriad internal data].

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