ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.2350G>A (p.Glu784Lys)

gnomAD frequency: 0.00001  dbSNP: rs147427999
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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 RCV000985960 SCV000963822 uncertain significance not provided 2025-01-14 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 784 of the POLE protein (p.Glu784Lys). This variant is present in population databases (rs147427999, 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: 664819). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985960 SCV001134700 uncertain significance not provided 2019-01-03 criteria provided, single submitter clinical testing
GeneDx RCV000985960 SCV001872768 uncertain significance not provided 2023-04-12 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; This variant is associated with the following publications: (PMID: 20951805)
Ambry Genetics RCV002442764 SCV002734431 uncertain significance Hereditary cancer-predisposing syndrome 2024-03-24 criteria provided, single submitter clinical testing The p.E784K variant (also known as c.2350G>A), located in coding exon 21 of the POLE gene, results from a G to A substitution at nucleotide position 2350. The glutamic acid at codon 784 is replaced by lysine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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