ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.574A>T (p.Ile192Phe) (rs768006988)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000548934 SCV000625438 uncertain significance Hereditary nonpolyposis colon cancer 2017-06-03 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with phenylalanine at codon 192 of the MSH2 protein (p.Ile192Phe). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and phenylalanine. This variant is present in population databases (rs768006988, ExAC 0.001%). 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: "Deleterious"; 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.
Color RCV000774556 SCV000908277 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-12 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001193998 SCV001363214 uncertain significance not specified 2019-03-26 criteria provided, single submitter clinical testing Variant summary: MSH2 c.574A>T (p.Ile192Phe) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, connector domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 246238 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.574A>T in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submission from a clinical diagnostic laboratory (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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