ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.4375G>C (p.Glu1459Gln)

gnomAD frequency: 0.00001  dbSNP: rs778238908
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001776651 SCV002013372 uncertain significance not provided 2021-05-06 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function
Labcorp Genetics (formerly Invitae), Labcorp RCV001776651 SCV002180267 uncertain significance not provided 2022-08-31 criteria provided, single submitter clinical testing 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 1320672). This variant has not been reported in the literature in individuals affected with POLE-related conditions. This variant is present in population databases (rs778238908, gnomAD 0.0009%). This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 1459 of the POLE protein (p.Glu1459Gln).
Ambry Genetics RCV003163914 SCV003911776 uncertain significance Hereditary cancer-predisposing syndrome 2022-12-14 criteria provided, single submitter clinical testing The p.E1459Q variant (also known as c.4375G>C), located in coding exon 34 of the POLE gene, results from a G to C substitution at nucleotide position 4375. The glutamic acid at codon 1459 is replaced by glutamine, an amino acid with highly 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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