Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV003655006 | SCV000653243 | uncertain significance | not provided | 2023-12-30 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1289 of the POLE protein (p.Arg1289Cys). 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: 473626). 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 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 | RCV000566522 | SCV000671401 | uncertain significance | Hereditary cancer-predisposing syndrome | 2015-06-28 | criteria provided, single submitter | clinical testing | The p.R1289C variant (also known as c.3865C>T), located in coding exon 31 of the POLE gene, results from a C to T substitution at nucleotide position 3865. The arginine at codon 1289 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6422 samples (12844 alleles) with coverage at this position. This amino acid position is not well conserved in available vertebrate species. 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 p.R1289C remains unclear. |
| Mendelics | RCV000709259 | SCV000838690 | uncertain significance | Familial colorectal cancer | 2018-07-02 | criteria provided, single submitter | clinical testing |