ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.3495C>G (p.Asp1165Glu)

gnomAD frequency: 0.00001  dbSNP: rs753667513
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001776498 SCV002013117 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 has a deleterious effect on protein structure/function
Labcorp Genetics (formerly Invitae), Labcorp RCV001776498 SCV002206613 uncertain significance not provided 2022-08-31 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 1165 of the POLE protein (p.Asp1165Glu). This variant is present in population databases (rs753667513, gnomAD 0.0009%). 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: 1320519). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C35"). 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.
Ambry Genetics RCV003163913 SCV003898531 uncertain significance Hereditary cancer-predisposing syndrome 2022-12-14 criteria provided, single submitter clinical testing The p.D1165E variant (also known as c.3495C>G), located in coding exon 29 of the POLE gene, results from a C to G substitution at nucleotide position 3495. The aspartic acid at codon 1165 is replaced by glutamic acid, 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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