ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.3740C>T (p.Pro1247Leu)

gnomAD frequency: 0.00003  dbSNP: rs572986717
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000760005 SCV000543998 uncertain significance not provided 2024-12-24 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 1247 of the POLE protein (p.Pro1247Leu). This variant is present in population databases (rs572986717, gnomAD 0.02%). 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: 405683). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000760005 SCV000889746 uncertain significance not provided 2017-12-08 criteria provided, single submitter clinical testing
GeneDx RCV000760005 SCV001821156 uncertain significance not provided 2023-10-31 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign germline variant to our knowledge; This variant is associated with the following publications: (PMID: 29320758)
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000467312 SCV002584598 uncertain significance Colorectal cancer, susceptibility to, 12 2022-08-31 criteria provided, single submitter clinical testing The POLE c.3740C>T (p.Pro1247Leu) missense change has a maximum subpopulation frequency of 0.025% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with POLE-associated polyposis, FILS syndrome, or IMAGE-I syndrome. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Ambry Genetics RCV004943850 SCV005478849 likely benign Hereditary cancer-predisposing syndrome 2024-10-17 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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