Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV003327420 | SCV000653085 | uncertain significance | not provided | 2024-11-25 | criteria provided, single submitter | clinical testing | This sequence change affects codon 598 of the POLE mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the POLE protein. This variant also falls at the last nucleotide of exon 16, which is part of the consensus splice site for this exon. This variant is present in population databases (no rsID available, gnomAD 0.007%). 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: 473486). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 | RCV002404538 | SCV002714527 | uncertain significance | Hereditary cancer-predisposing syndrome | 2020-01-28 | criteria provided, single submitter | clinical testing | The c.1794G>A variant (also known as p.E598E), located in exon 16 of the POLE gene, results from a G to A substitution at nucleotide position 1794. This nucleotide substitution does not change the glutamic acid at codon 598. However, this change occurs in the last base pair of coding exon 16, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct experimental evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Gene |
RCV003327420 | SCV004034872 | uncertain significance | not provided | 2023-11-29 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown. |