Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000480582 | SCV000572429 | uncertain significance | not provided | 2016-12-06 | criteria provided, single submitter | clinical testing | This variant is denoted POLE c.4077G>T at the cDNA level, p.Arg1359Ser (R1359S) at the protein level, and results in the change of an Arginine to a Serine (AGG>AGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. POLE Arg1359Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Serine differ in some properties, this is considered a semi-conservative amino acid substitution. POLE Arg1359Ser occurs at a position where amino acids with properties similar to Arginine are tolerated across species and is not located in a known functional domain (Tahirov 2009, Preston 2010). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether POLE Arg1359Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. |
| Labcorp Genetics |
RCV000480582 | SCV000961583 | uncertain significance | not provided | 2024-07-01 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 1359 of the POLE protein (p.Arg1359Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with undergoing routine hereditary cancer testing (PMID: 32522261). ClinVar contains an entry for this variant (Variation ID: 422857). 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. |