ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1657A>G (p.Asn553Asp) (rs772772789)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000546300 SCV000625291 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-03-19 criteria provided, single submitter clinical testing This sequence change replaces asparagine with aspartic acid at codon 553 of the MSH2 protein (p.Asn553Asp). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a MSH2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant has uncertain impact on MSH2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Integrated Genetics/Laboratory Corporation of America RCV001193847 SCV001362993 uncertain significance not specified 2019-09-05 criteria provided, single submitter clinical testing Variant summary: MSH2 c.1657A>G (p.Asn553Asp) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, clamp domain (IPR007861) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251154 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.1657A>G in individuals affected with Hereditary Non-Polyposis Colon Cancer and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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