ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.1676G>A (p.Arg559Gln)

gnomAD frequency: 0.00003  dbSNP: rs766276875
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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 RCV001558542 SCV000772763 uncertain significance not provided 2025-01-02 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 559 of the POLE protein (p.Arg559Gln). This variant is present in population databases (rs766276875, gnomAD 0.03%). This missense change has been observed in individual(s) with prostate cancer (PMID: 27701467). ClinVar contains an entry for this variant (Variation ID: 540798). 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%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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 RCV001558542 SCV001780511 uncertain significance not provided 2025-01-27 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with prostate cancer (PMID: 27701467); This variant is associated with the following publications: (PMID: 20951805, 27701467)
GenomeConnect, ClinGen RCV001558542 SCV002074978 not provided not provided no assertion provided phenotyping only Variant interpreted as Uncertain significance and reported on 09-25-2020 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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