ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.464T>G (p.Val155Gly) (rs876658188)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000562713 SCV000662336 uncertain significance Hereditary cancer-predisposing syndrome 2017-02-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000562713 SCV000690111 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781569 SCV000919721 uncertain significance not specified 2018-11-13 criteria provided, single submitter clinical testing Variant summary: MSH2 c.464T>G (p.Val155Gly) 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 246240 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.464T>G in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000527224 SCV000625428 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-14 criteria provided, single submitter clinical testing This sequence change replaces valine with glycine at codon 155 of the MSH2 protein (p.Val155Gly). The valine residue is weakly conserved and there is a moderate physicochemical difference between valine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 455593). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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