ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.2339C>T (p.Ser780Leu)

gnomAD frequency: 0.00002  dbSNP: rs778288256
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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 RCV001591067 SCV000544011 uncertain significance not provided 2025-01-26 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 780 of the POLE protein (p.Ser780Leu). This variant is present in population databases (rs778288256, gnomAD 0.006%). 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: 405696). 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.
GeneDx RCV001591067 SCV001823562 uncertain significance not provided 2025-01-09 criteria provided, single submitter clinical testing 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)
PreventionGenetics, part of Exact Sciences RCV004737499 SCV005367452 uncertain significance POLE-related disorder 2024-06-03 no assertion criteria provided clinical testing The POLE c.2339C>T variant is predicted to result in the amino acid substitution p.Ser780Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD and is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/405696/). 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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