ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.4812G>C (p.Glu1604Asp)

gnomAD frequency: 0.00001  dbSNP: rs1064794898
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000486541 SCV000570175 uncertain significance not provided 2022-12-23 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: 29056344)
Labcorp Genetics (formerly Invitae), Labcorp RCV000486541 SCV000772652 uncertain significance not provided 2024-12-02 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 1604 of the POLE protein (p.Glu1604Asp). This variant is not present in population databases (gnomAD no frequency). 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: 421083). 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.
Ambry Genetics RCV002341142 SCV002635017 uncertain significance Hereditary cancer-predisposing syndrome 2024-06-22 criteria provided, single submitter clinical testing The p.E1604D variant (also known as c.4812G>C), located in coding exon 37 of the POLE gene, results from a G to C substitution at nucleotide position 4812. The glutamic acid at codon 1604 is replaced by aspartic 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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