ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.6796G>A (p.Gly2266Ser)

gnomAD frequency: 0.00002  dbSNP: rs200911338
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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 RCV003324736 SCV000289484 uncertain significance not provided 2024-10-30 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2266 of the POLE protein (p.Gly2266Ser). This variant is present in population databases (rs200911338, 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: 240620). 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.
Fulgent Genetics, Fulgent Genetics RCV002500795 SCV002814775 uncertain significance Colorectal cancer, susceptibility to, 12; Facial dysmorphism-immunodeficiency-livedo-short stature syndrome; Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency 2022-04-02 criteria provided, single submitter clinical testing
GeneDx RCV003324736 SCV004030649 uncertain significance not provided 2023-08-27 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
PreventionGenetics, part of Exact Sciences RCV004529409 SCV004108116 uncertain significance POLE-related disorder 2023-04-27 criteria provided, single submitter clinical testing The POLE c.6796G>A variant is predicted to result in the amino acid substitution p.Gly2266Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-133201348-C-T). It is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/240620/). 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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