ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.1744C>T (p.Leu582Phe)

gnomAD frequency: 0.00001  dbSNP: rs761273376
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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 RCV000607919 SCV000731467 uncertain significance not specified 2017-03-20 criteria provided, single submitter clinical testing The p.Leu582Phe variant in POLE has not been previously reported in individuals with colorectal cancer, but has been identified in 1/16512 South Asian chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs761273376). Computational prediction tools and conservation analysis do no t provide strong support for or against an impact to the protein. In summary, th e clinical significance of the p.Leu582Phe variant is uncertain.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759980 SCV000889715 uncertain significance not provided 2018-01-13 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000759980 SCV001213417 uncertain significance not provided 2024-12-09 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 582 of the POLE protein (p.Leu582Phe). This variant is present in population databases (rs761273376, gnomAD 0.006%). 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: 517271). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt POLE protein function with a negative 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 RCV000759980 SCV005325487 uncertain significance not provided 2023-10-04 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 20951805)

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