ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.2113C>T (p.Arg705Trp)

gnomAD frequency: 0.00001  dbSNP: rs200621883
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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 RCV001564506 SCV000772720 uncertain significance not provided 2025-02-04 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 705 of the POLE protein (p.Arg705Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 540760). 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 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.
Fulgent Genetics, Fulgent Genetics RCV000763811 SCV000894728 uncertain significance Colorectal cancer, susceptibility to, 12; Facial dysmorphism-immunodeficiency-livedo-short stature syndrome 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV001564506 SCV001787683 uncertain significance not provided 2020-06-16 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as a pathogenic or benign germline variant to our knowledge; This variant is associated with the following publications: (PMID: 31829442, 29625053, 29056344, 28481359)
Ambry Genetics RCV002422402 SCV002725983 uncertain significance Hereditary cancer-predisposing syndrome 2021-07-16 criteria provided, single submitter clinical testing The p.R705W variant (also known as c.2113C>T), located in coding exon 19 of the POLE gene, results from a C to T substitution at nucleotide position 2113. The arginine at codon 705 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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