ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.1447A>G (p.Thr483Ala)

gnomAD frequency: 0.00001  dbSNP: rs777736640
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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 RCV000985948 SCV000653054 uncertain significance not provided 2025-01-06 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 483 of the POLE protein (p.Thr483Ala). This variant is present in population databases (rs777736640, gnomAD 0.003%). 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: 473457). 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.
Ambry Genetics RCV000566947 SCV000674326 uncertain significance Hereditary cancer-predisposing syndrome 2023-08-15 criteria provided, single submitter clinical testing The p.T483A variant (also known as c.1447A>G), located in coding exon 14 of the POLE gene, results from an A to G substitution at nucleotide position 1447. The threonine at codon 483 is replaced by alanine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985948 SCV001134681 uncertain significance not provided 2019-07-03 criteria provided, single submitter clinical testing
GeneDx RCV000985948 SCV002601010 uncertain significance not provided 2023-05-17 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
Baylor Genetics RCV000544703 SCV004203531 uncertain significance Colorectal cancer, susceptibility to, 12 2023-09-26 criteria provided, single submitter clinical testing

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