ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.4680C>G (p.Asp1560Glu)

gnomAD frequency: 0.00003  dbSNP: rs774425403
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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 RCV001753702 SCV000289398 uncertain significance not provided 2024-12-02 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 1560 of the POLE protein (p.Asp1560Glu). This variant is present in population databases (rs774425403, gnomAD 0.006%). This missense change has been observed in individual(s) with breast cancer (PMID: 35534704). ClinVar contains an entry for this variant (Variation ID: 240534). 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 RCV001753702 SCV001996410 uncertain significance not provided 2019-09-26 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics RCV002338741 SCV002636271 uncertain significance Hereditary cancer-predisposing syndrome 2021-10-18 criteria provided, single submitter clinical testing The p.D1560E variant (also known as c.4680C>G), located in coding exon 36 of the POLE gene, results from a C to G substitution at nucleotide position 4680. The aspartic acid at codon 1560 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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