ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.461G>A (p.Arg154Lys)

gnomAD frequency: 0.00004  dbSNP: rs769882912
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000657072 SCV000293354 uncertain significance not provided 2024-06-17 criteria provided, single submitter clinical testing In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in individuals with ovarian cancer and in a control population (PMID: 32546565); This variant is associated with the following publications: (PMID: 32546565)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000236272 SCV000602054 uncertain significance not specified 2017-06-01 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000657072 SCV000653305 uncertain significance not provided 2025-02-02 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 154 of the POLE protein (p.Arg154Lys). This variant is present in population databases (rs769882912, gnomAD 0.006%). 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: 246050). 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 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.
Ambry Genetics RCV000566605 SCV000671341 likely benign Hereditary cancer-predisposing syndrome 2015-06-28 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
PreventionGenetics, part of Exact Sciences RCV000657072 SCV000806788 uncertain significance not provided 2017-10-10 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV005003589 SCV005633774 uncertain significance Colorectal cancer, susceptibility to, 12; Facial dysmorphism-immunodeficiency-livedo-short stature syndrome; Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency 2024-04-01 criteria provided, single submitter clinical testing

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