ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.2375A>G (p.Lys792Arg)

dbSNP: rs2042772263
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001587225 SCV001379088 uncertain significance not provided 2022-12-17 criteria provided, single submitter clinical testing 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. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 938497). This variant has not been reported in the literature in individuals affected with POLE-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 792 of the POLE protein (p.Lys792Arg).
GeneDx RCV001587225 SCV001816294 uncertain significance not provided 2020-03-04 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); Has not been previously published as a pathogenic or benign germline variant to our knowledge; Protein-based in silico analysis supports a deleterious effect. In addition, splice predictors suggest this variant may impact gene splicing. In the absence of RNA or functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 28577310)
PreventionGenetics, part of Exact Sciences RCV003973141 SCV004794974 uncertain significance POLE-related condition 2024-01-04 criteria provided, single submitter clinical testing The POLE c.2375A>G variant is predicted to result in the amino acid substitution p.Lys792Arg. To our knowledge, this variant has not been reported as a germline variant in the literature or in a large population database, indicating this variant is rare. This variant is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/938497/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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