ClinVar Miner

Submissions for variant NM_006231.3(POLE):c.1354C>A (p.Pro452Thr) (rs1555228573)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000552875 SCV000653049 uncertain significance Colorectal cancer, susceptibility to, 12 2017-10-24 criteria provided, single submitter clinical testing This sequence change replaces proline with threonine at codon 452 of the POLE protein (p.Pro452Thr). The proline residue is highly conserved and there is a small physicochemical difference between proline and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with POLE-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: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Integrated Genetics/Laboratory Corporation of America RCV000781764 SCV000920075 uncertain significance not specified 2018-09-14 criteria provided, single submitter clinical testing Variant summary: POLE c.1354C>A (p.Pro452Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 243954 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.1354C>A in individuals affected with Colorectal Cancer 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.
Ambry Genetics RCV001011142 SCV001171431 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-12 criteria provided, single submitter clinical testing Insufficient evidence

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