ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.2888G>A (p.Gly963Asp)

gnomAD frequency: 0.00002  dbSNP: rs777454763
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV003320642 SCV000544089 uncertain significance not provided 2025-01-30 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 963 of the POLE protein (p.Gly963Asp). This variant is present in population databases (rs777454763, gnomAD 0.01%). 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: 405768). 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 RCV000463786 SCV001737488 uncertain significance Colorectal cancer, susceptibility to, 12 2021-05-06 criteria provided, single submitter clinical testing The POLE c.2888G>A (p.Gly963Asp) missense change has a maximum subpopulation frequency of 0.014% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/12-133237727-C-T?dataset=gnomad_r2_1). Six of seven in silico tools predict a deleterious effect of this variant on protein function (PP3), but to our knowledge these predictions have not been confirmed by functional assays. This variant is not located in the exonuclease domain where many disease-causing mutations are known to occur. 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: PP3.
Ambry Genetics RCV002436396 SCV002750816 uncertain significance Hereditary cancer-predisposing syndrome 2023-12-29 criteria provided, single submitter clinical testing The p.G963D variant (also known as c.2888G>A), located in coding exon 25 of the POLE gene, results from a G to A substitution at nucleotide position 2888. The glycine at codon 963 is replaced by aspartic acid, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV003320642 SCV004025557 uncertain significance not provided 2024-02-27 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; This variant is associated with the following publications: (PMID: 29056344, 20951805)

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