ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.6392G>A (p.Arg2131His)

gnomAD frequency: 0.00003  dbSNP: rs141954509
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV002244932 SCV000543896 uncertain significance not provided 2023-12-26 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 2131 of the POLE protein (p.Arg2131His). This variant is present in population databases (rs141954509, 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: 405590). 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000608569 SCV000712801 uncertain significance not specified 2017-02-06 criteria provided, single submitter clinical testing The p.Arg2131His variant in POLE has not been previously reported in individuals with colorectal cancer, but has been identified in 1/8600 of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/ EVS/; dbSNP rs141954509). Computational prediction tools and conservation analys is suggest that the p.Arg2131His variant may impact the protein, though this inf ormation is not predictive enough to determine pathogenicity. In summary, the cl inical significance of the p.Arg2131His variant is uncertain.
GeneDx RCV002244932 SCV002513068 uncertain significance not provided 2023-02-28 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; Has not been previously published as pathogenic or benign to our knowledge

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