ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.5591T>C (p.Ile1864Thr)

gnomAD frequency: 0.00001  dbSNP: rs896266569
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001551224 SCV000653383 uncertain significance not provided 2024-01-05 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1864 of the POLE protein (p.Ile1864Thr). This variant is present in population databases (no rsID available, 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: 473748). 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 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000614590 SCV000731328 uncertain significance not specified 2016-12-28 criteria provided, single submitter clinical testing The p.Ile1864Thr variant in POLE has not been previously reported in individuals with colorectal cancer and was absent from large population studies. Computatio nal prediction tools and conservation analysis suggest that the p.Ile1864Thr var iant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Ile1864 Thr variant is uncertain.
GeneDx RCV001551224 SCV001771688 uncertain significance not provided 2023-09-06 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

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