ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.2927G>A (p.Arg976His)

gnomAD frequency: 0.00001  dbSNP: rs878854857
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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 RCV002281074 SCV000289312 uncertain significance not provided 2024-11-06 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 976 of the POLE protein (p.Arg976His). This variant is present in population databases (no rsID available, gnomAD 0.02%). 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: 240448). 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 expected to disrupt POLE protein function with a positive 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 RCV002281074 SCV002569813 uncertain significance not provided 2024-02-28 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 a patient with head and neck carcinomas (HNSCC) (PMID: 34598035); This variant is associated with the following publications: (PMID: 20951805, 34598035)
Ambry Genetics RCV002436032 SCV002752386 uncertain significance Hereditary cancer-predisposing syndrome 2024-12-06 criteria provided, single submitter clinical testing The p.R976H variant (also known as c.2927G>A), located in coding exon 25 of the POLE gene, results from a G to A substitution at nucleotide position 2927. The arginine at codon 976 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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