ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.3850C>T (p.Arg1284Trp)

gnomAD frequency: 0.00001  dbSNP: rs753426630
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001843520 SCV000544084 uncertain significance not provided 2024-12-26 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 1284 of the POLE protein (p.Arg1284Trp). This variant is present in population databases (rs753426630, gnomAD 0.02%). 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: 405763). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on POLE protein function. 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 RCV001843520 SCV002102655 uncertain significance not provided 2022-03-04 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
Ambry Genetics RCV002365613 SCV002623669 uncertain significance Hereditary cancer-predisposing syndrome 2022-10-27 criteria provided, single submitter clinical testing The p.R1284W variant (also known as c.3850C>T), located in coding exon 31 of the POLE gene, results from a C to T substitution at nucleotide position 3850. The arginine at codon 1284 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV002506103 SCV002816942 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 2021-07-23 criteria provided, single submitter clinical testing

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