Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000566122 | SCV000671464 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-01-03 | criteria provided, single submitter | clinical testing | The p.P441L variant (also known as c.1322C>T), located in coding exon 13 of the POLE gene, results from a C to T substitution at nucleotide position 1322. The proline at codon 441 is replaced by leucine, an amino acid with similar properties. This alteration was observed in 1/431 individuals with microsatellite stable colorectal cancer (Stenzinger A et al. Cancer Med. 2014 Dec;3:1527-38). It was also reported in a 64 year old male with Lynch-like syndrome (LLS) in a cohort of 81 patients with LLS and 47 patients with Lynch syndrome who all had mismatch repair deficient colorectal cancer (Xu Y et al. Front Genet, 2020 Aug;11:991)This amino acid position is highly conserved in available vertebrate species. 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. |
| Labcorp Genetics |
RCV001764670 | SCV000825026 | uncertain significance | not provided | 2024-07-22 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 441 of the POLE protein (p.Pro441Leu). This variant is present in population databases (rs775340163, gnomAD 0.003%). 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: 484468). 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 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. |
| Gene |
RCV001764670 | SCV001997831 | uncertain significance | not provided | 2019-09-30 | criteria provided, single submitter | clinical testing | Not observed at a 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; This variant is associated with the following publications: (PMID: 25124163, 29572003, 29320758, 26763250) |