ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2661C>G (p.Phe887Leu) (rs1290935051)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000526536 SCV000625402 uncertain significance Hereditary nonpolyposis colon cancer 2019-10-29 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 887 of the MSH2 protein (p.Phe887Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is not present in population databases (ExAC no frequency) and 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: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
Integrated Genetics/Laboratory Corporation of America RCV001193289 SCV001362024 uncertain significance not specified 2019-06-03 criteria provided, single submitter clinical testing Variant summary: MSH2 c.2661C>G (p.Phe887Leu) results in a non-conservative amino acid change in 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 1.2e-05 in 251088 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.2661C>G in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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