ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.4609C>T (p.Leu1537Phe)

gnomAD frequency: 0.00001  dbSNP: rs1418237375
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002466591 SCV000957225 uncertain significance not provided 2025-01-30 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 1537 of the POLE protein (p.Leu1537Phe). This variant is present in population databases (no rsID available, gnomAD 0.004%). 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: 659669). 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000816706 SCV001737483 uncertain significance Colorectal cancer, susceptibility to, 12 2021-06-03 criteria provided, single submitter clinical testing The POLE c.4609C>T (p.Leu1537Phe) missense change has a maximum subpopulation frequency of 0.0040% in gnomAD v2.1.1 (PM2_Supporting; https://gnomad.broadinstitute.org/variant/12-133219525-G-A?dataset=gnomad_r2_1). Five of seven in silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional assays. This variant has been identified in a tumor with low tumor mutational burden (internal data). To our knowledge, this variant has not been reported in the literature in individuals with POLE-related disease. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_Supporting, BP4.
GeneDx RCV002466591 SCV002762577 uncertain significance not provided 2022-12-06 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: 29056344)

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