ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.109C>T (p.Arg37Trp)

gnomAD frequency: 0.00001  dbSNP: rs753101641
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001771900 SCV000772641 uncertain significance not provided 2024-12-30 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 37 of the POLE protein (p.Arg37Trp). This variant is present in population databases (rs753101641, 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: 540690). 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.
GeneDx RCV001771900 SCV001992952 uncertain significance not provided 2021-11-30 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV002268236 SCV002550226 uncertain significance not specified 2025-03-04 criteria provided, single submitter clinical testing
MGZ Medical Genetics Center RCV000650792 SCV002579238 uncertain significance Colorectal cancer, susceptibility to, 12 2021-07-27 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002485467 SCV002785317 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 2021-08-26 criteria provided, single submitter clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000650792 SCV005402243 uncertain significance Colorectal cancer, susceptibility to, 12 2024-01-23 criteria provided, single submitter clinical testing The POLE c.109C>T (p.Arg37Trp) missense change has a maximum subpopulation frequency of 0.0065% 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 Functional studies have not been performed. 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.

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