Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001420964 | SCV001623443 | uncertain significance | not specified | 2021-05-17 | criteria provided, single submitter | clinical testing | Variant summary: POLE c.1231G>T (p.Val411Leu) results in a conservative amino acid change located in the DNA-directed DNA polymerase, family B, exonuclease domain (IPR006133) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250666 control chromosomes (gnomAD). To our knowledge, no germline occurrence of c.1231G>T in individuals affected with Colorectal Cancer has been reported. However, several somatic occurrences of this variant have been reported in the literature (example: PMID: 33727829, 33569431, 32810930). In 3->5 exonuclease activity assay the variant showed reduced activity compared to wild-type (Shinbrot_2014). One ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic in somatic state. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |
| Labcorp Genetics |
RCV003766183 | SCV004682142 | uncertain significance | not provided | 2023-08-27 | criteria provided, single submitter | clinical testing | 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on POLE function (PMID: 25228659, 29352080). 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. ClinVar contains an entry for this variant (Variation ID: 376503). This missense change has been observed in individuals with colonic polyposis and colorectal cancer (PMID: 27573199; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 411 of the POLE protein (p.Val411Leu). |
| Database of Curated Mutations |
RCV000424174 | SCV000507161 | likely pathogenic | Gastric adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
| Database of Curated Mutations |
RCV000434429 | SCV000507162 | likely pathogenic | Neoplasm of the large intestine | 2016-05-31 | no assertion criteria provided | literature only | |
| Database of Curated Mutations |
RCV000441211 | SCV000507163 | likely pathogenic | Glioblastoma | 2016-05-31 | no assertion criteria provided | literature only | |
| Database of Curated Mutations |
RCV000423521 | SCV000507164 | likely pathogenic | Malignant neoplasm of body of uterus | 2016-05-31 | no assertion criteria provided | literature only |