ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.2459T>C (p.Met820Thr)

gnomAD frequency: 0.00001  dbSNP: rs767460640
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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 RCV003128650 SCV000831858 uncertain significance not provided 2024-09-21 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 820 of the POLE protein (p.Met820Thr). This variant is present in population databases (rs767460640, 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: 579641). 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 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 RCV003128650 SCV003805910 uncertain significance not provided 2023-02-09 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with breast cancer (Dominguez-Valentin et al., 2018); This variant is associated with the following publications: (PMID: 20951805, 29056344, 29371908)
PreventionGenetics, part of Exact Sciences RCV004535748 SCV004120424 uncertain significance POLE-related disorder 2024-07-22 no assertion criteria provided clinical testing The POLE c.2459T>C variant is predicted to result in the amino acid substitution p.Met820Thr. This variant has been reported in a cohort study of individuals with breast and/or gynecological cancer: however, no clinical details were provided (Table 2, Dominguez-Valentin et al. 2018. PubMed ID: 29371908). This variant is reported in 2 of ~251,000 alleles in gnomAD, and is interpreted as a variant of uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/579641/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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