ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.665G>A (p.Arg222His)

gnomAD frequency: 0.00001  dbSNP: rs1060500862
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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 RCV000485092 SCV000544146 uncertain significance not provided 2024-11-13 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 222 of the POLE protein (p.Arg222His). This variant is present in population databases (no rsID available, gnomAD 0.003%). 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: 405821). 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 RCV000485092 SCV000569880 uncertain significance not provided 2023-02-14 criteria provided, single submitter clinical testing Identified as a somatic variant in a patient with adult T cell leukemia/lymphoma in published literature (Kataoka et al., 2015); 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; This variant is associated with the following publications: (PMID: 26437031)
Ambry Genetics RCV004943862 SCV005478884 uncertain significance Hereditary cancer-predisposing syndrome 2024-12-04 criteria provided, single submitter clinical testing The p.R222H variant (also known as c.665G>A), located in coding exon 7 of the POLE gene, results from a G to A substitution at nucleotide position 665. The arginine at codon 222 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.

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