Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000607462 | SCV000712877 | uncertain significance | not specified | 2017-02-26 | criteria provided, single submitter | clinical testing | The p.Gly970Ser variant in POLE has not been previously reported in individuals with colorectal cancer or in large population studies. Computational prediction tools and conservation analysis suggest that the p.Gly970Ser variant may impact the protein, though this information is not predictive enough to determine patho genicity. In summary, the clinical significance of the p.Gly970Ser variant is un certain. |
| Invitae | RCV003655141 | SCV000833227 | uncertain significance | not provided | 2024-01-10 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 970 of the POLE protein (p.Gly970Ser). This variant is not present in population databases (gnomAD no frequency). 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: 505569). 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. |
| Genetic Services Laboratory, |
RCV000607462 | SCV002070195 | uncertain significance | not specified | 2020-03-02 | criteria provided, single submitter | clinical testing | DNA sequence analysis of the POLE gene demonstrated a sequence change, c.2908G>A, in exon 25 that results in an amino acid change, p.Gly970Ser. This sequence change does not appear to have been previously described in patients with POLE-related disorders. This sequence change is absent from the large population databases (ExAC and gnomAD). The p.Gly970Ser change affects a highly conserved amino acid residue located in a domain of the POLE protein that is known to be functional. The p.Gly970Ser substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Gly970Ser change remains unknown at this time. |
| Ambry Genetics | RCV002438548 | SCV002750943 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-10-05 | criteria provided, single submitter | clinical testing | The p.G970S variant (also known as c.2908G>A), located in coding exon 25 of the POLE gene, results from a G to A substitution at nucleotide position 2908. The glycine at codon 970 is replaced by serine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |