ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.286C>T (p.Arg96Cys) (rs1443234544)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000580951 SCV000685075 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-13 criteria provided, single submitter clinical testing
Invitae RCV000629862 SCV000750818 uncertain significance Hereditary nonpolyposis colon cancer 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 96 of the MSH2 protein (p.Arg96Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with extramammary Paget disease (PMID: 27487738). 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 RCV000580951 SCV001177725 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-11 criteria provided, single submitter clinical testing Insufficient evidence
Liquid Biopsy and Precision Medicine Group,Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research RCV001090210 SCV001245508 uncertain significance Breast-ovarian cancer, familial 1 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001193290 SCV001362025 uncertain significance not specified 2019-07-26 criteria provided, single submitter clinical testing Variant summary: MSH2 c.286C>T (p.Arg96Cys) results in a non-conservative amino acid change located in the N-terminal 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 4e-06 in 251282 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.286C>T has been reported in the literature in one individual affected with Extramammary Paget Disease (EMPD; Kang_2016). This report does not provide unequivocal conclusions about association of the variant with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar (after 2014) and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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