ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.154C>T (p.Arg52Trp)

gnomAD frequency: 0.00016  dbSNP: rs115452881
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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000759976 SCV000289259 uncertain significance not provided 2024-02-01 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 52 of the POLE protein (p.Arg52Trp). This variant is present in population databases (rs115452881, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer (PMID: 35264596). ClinVar contains an entry for this variant (Variation ID: 240396). 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 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.
Mendelics RCV003492006 SCV000838711 likely benign Hereditary cancer 2024-01-23 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759976 SCV000889709 uncertain significance not provided 2017-10-07 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000763823 SCV000894740 uncertain significance Colorectal cancer, susceptibility to, 12; Facial dysmorphism-immunodeficiency-livedo-short stature syndrome 2018-10-31 criteria provided, single submitter clinical testing
Baylor Genetics RCV000232236 SCV001481315 uncertain significance Colorectal cancer, susceptibility to, 12 2020-12-13 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx RCV000759976 SCV002522123 uncertain significance not provided 2022-05-13 criteria provided, single submitter clinical testing 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 germline variant to our knowledge; This variant is associated with the following publications: (PMID: 30849372)
Sema4, Sema4 RCV000758172 SCV002536756 likely benign Hereditary cancer-predisposing syndrome 2020-10-12 criteria provided, single submitter curation
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000232236 SCV002584674 uncertain significance Colorectal cancer, susceptibility to, 12 2022-09-28 criteria provided, single submitter clinical testing The POLE c.154C>T (p.Arg52Trp) missense change has a maximum subpopulation frequency of 0.025% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. To our knowledge, this variant has not been reported in the literature in individuals with POLE-related disease. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Mayo Clinic Laboratories, Mayo Clinic RCV000759976 SCV004226398 uncertain significance not provided 2022-06-30 criteria provided, single submitter clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV003493544 SCV004243026 uncertain significance not specified 2024-02-06 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003907878 SCV004719996 uncertain significance POLE-related condition 2023-12-05 criteria provided, single submitter clinical testing The POLE c.154C>T variant is predicted to result in the amino acid substitution p.Arg52Trp. This variant has been reported in a cohort of individuals with a history breast cancer, but was interpreted as uncertain (Supplementary Table 3, Guindalini et al. 2022. PubMed ID: 35264596). This variant is reported in 0.025% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as uncertain significance by the vast majority of submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/240396/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
True Health Diagnostics RCV000758172 SCV000886708 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-12 no assertion criteria provided clinical testing

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