ClinVar Miner

Submissions for variant NM_006231.3(POLE):c.167C>T (p.Pro56Leu) (rs1555230404)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000535231 SCV000653076 uncertain significance Colorectal cancer, susceptibility to, 12 2019-04-24 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 56 of the POLE protein (p.Pro56Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. 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. ClinVar contains an entry for this variant (Variation ID: 473478). 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, 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.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000825440 SCV000966738 uncertain significance not specified 2018-10-18 criteria provided, single submitter clinical testing The p.Pro56Leu variant in POLE has not been reported in the literature in indivi duals with hereditary colorectal cancer, but has been reported by other clinical laboratories in ClinVar (Variation ID: 473478). This variant was absent from la rge population databases. Computational prediction tools and conservation analys is do not provide strong support for or against an impact to the protein. In sum mary, the clinical significance of the p.Pro56Leu variant is uncertain. ACMG/AMP Criteria applied: PM2.

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