ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.1550C>T (p.Pro517Leu)

gnomAD frequency: 0.00001  dbSNP: rs780556141
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000603876 SCV000731332 uncertain significance not specified 2016-12-28 criteria provided, single submitter clinical testing The p.Pro517Leu variant in POLE has not been previously reported in individuals with colorectal cancer, but has been identified in 1/66194 of European chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs780556141). Computational prediction tools and conservation analysis sugge st that the p.Pro517Leu variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical si gnificance of the p.Pro517Leu variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp RCV001559068 SCV000772603 uncertain significance not provided 2024-01-09 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 517 of the POLE protein (p.Pro517Leu). This variant is present in population databases (rs780556141, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with POLE-related conditions. ClinVar contains an entry for this variant (Variation ID: 517195). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt POLE protein function with a positive predictive value of 80%. 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.
GeneDx RCV001559068 SCV001781139 uncertain significance not provided 2020-12-24 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with ovarian cancer (Song 2020); This variant is associated with the following publications: (PMID: 32546565)
GenomeConnect - Invitae Patient Insights Network RCV003483688 SCV004228564 not provided Colorectal cancer, susceptibility to, 12; Facial dysmorphism-immunodeficiency-livedo-short stature syndrome no assertion provided phenotyping only Variant interpreted as Uncertain significance and reported on 07-10-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

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