ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.1181A>G (p.Gln394Arg)

gnomAD frequency: 0.00002  dbSNP: rs1014444345
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985944 SCV001134676 uncertain significance not provided 2018-09-11 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000985944 SCV001229985 uncertain significance not provided 2024-04-30 criteria provided, single submitter clinical testing This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 394 of the POLE protein (p.Gln394Arg). This variant is present in population databases (no rsID available, gnomAD 0.008%). 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: 801256). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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 RCV000985944 SCV001814247 uncertain significance not provided 2022-08-23 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter 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, 20951805)
Ambry Genetics RCV002337042 SCV002636848 uncertain significance Hereditary cancer-predisposing syndrome 2023-04-07 criteria provided, single submitter clinical testing The p.Q394R variant (also known as c.1181A>G), located in coding exon 12 of the POLE gene, results from an A to G substitution at nucleotide position 1181. The glutamine at codon 394 is replaced by arginine, 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics RCV001065047 SCV004203546 uncertain significance Colorectal cancer, susceptibility to, 12 2023-08-03 criteria provided, single submitter clinical testing

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