ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.4892G>A (p.Arg1631His)

gnomAD frequency: 0.00009  dbSNP: rs775590365
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000760019 SCV000289407 uncertain significance not provided 2025-01-21 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1631 of the POLE protein (p.Arg1631His). This variant is present in population databases (rs775590365, gnomAD 0.005%). 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: 240543). 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 RCV000760019 SCV000570457 uncertain significance not provided 2024-09-17 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; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 29056344)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000760019 SCV000889761 uncertain significance not provided 2020-03-05 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV002257585 SCV002536867 uncertain significance Hereditary cancer-predisposing syndrome 2021-04-10 criteria provided, single submitter curation
Ambry Genetics RCV002257585 SCV003891271 uncertain significance Hereditary cancer-predisposing syndrome 2024-05-28 criteria provided, single submitter clinical testing The c.4892G>A (p.R1631H) alteration is located in exon 37 (coding exon 37) of the POLE gene. This alteration results from a G to A substitution at nucleotide position 4892, causing the arginine (R) at amino acid position 1631 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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