ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2754G>C (p.Lys918Asn) (rs1553370893)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000532962 SCV000625409 uncertain significance Hereditary nonpolyposis colon cancer 2017-06-23 criteria provided, single submitter clinical testing This sequence change replaces lysine with asparagine at codon 918 of the MSH2 protein (p.Lys918Asn). The lysine residue is weakly conserved and there is a moderate physicochemical difference between lysine and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with an MSH2-related disease. 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Ambry Genetics RCV001016506 SCV001177466 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-19 criteria provided, single submitter clinical testing Insufficient evidence
Integrated Genetics/Laboratory Corporation of America RCV001193292 SCV001362028 uncertain significance not specified 2019-08-16 criteria provided, single submitter clinical testing Variant summary: MSH2 c.2754G>C (p.Lys918Asn) 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 was absent in 248492 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2754G>C has been reported in the literature in an individual affected with endometrial carcinoma (Karnezis_2016). This report does not provide an unequivocal conclusion about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission (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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