ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.6775C>T (p.Arg2259Trp)

gnomAD frequency: 0.00001  dbSNP: rs866548835
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000486001 SCV000570421 uncertain significance not provided 2023-01-30 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 an individual with breast and thyroid cancer (Pinheiro et al., 2020); This variant is associated with the following publications: (PMID: 28873162, 32443704)
Labcorp Genetics (formerly Invitae), Labcorp RCV000486001 SCV000653459 uncertain significance not provided 2024-12-26 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 2259 of the POLE protein (p.Arg2259Trp). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer (PMID: 35534704). ClinVar contains an entry for this variant (Variation ID: 421275). 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.
CeGaT Center for Human Genetics Tuebingen RCV000486001 SCV001502156 likely benign not provided 2023-10-01 criteria provided, single submitter clinical testing POLE: BP4
Mendelics RCV003492071 SCV004232575 likely benign Hereditary cancer 2024-01-23 criteria provided, single submitter clinical testing

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