ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2018C>T (p.Pro673Leu) (rs864622085)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000204190 SCV000259297 uncertain significance Lynch syndrome 2015-07-06 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 673 of the MSH6 protein (p.Pro673Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. This variant has not been published in the literature and is not present in population databases. 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. In summary, this is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000569723 SCV000662489 uncertain significance Hereditary cancer-predisposing syndrome 2016-07-07 criteria provided, single submitter clinical testing Insufficient evidence
Integrated Genetics/Laboratory Corporation of America RCV001174913 SCV001338347 uncertain significance not specified 2020-02-10 criteria provided, single submitter clinical testing Variant summary: MSH6 c.2018C>T (p.Pro673Leu) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, connector domain (IPR007860) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250906 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.2018C>T in individuals affected with Hereditary Non-Polyposis Colon Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color RCV000569723 SCV001352806 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-12 criteria provided, single submitter clinical testing

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