Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001031427 | SCV001194733 | uncertain significance | Colorectal cancer, susceptibility to, 12 | 2019-01-17 | criteria provided, single submitter | clinical testing | This variant is an in-frame deletion of the genomic region encompassing exons 9-16 of the POLE gene. It preserves the integrity of the reading frame. This variant has not been reported in the literature in individuals with POLE-related conditions. This variant deletes 331 amino acid residues (p.Asp268-Glu598) of the POLE protein, encompassing the entire exonuclease domain (residues 268-471) (PMID: 23447401). It is expected to result in severe disruption of the POLE protein and loss of protein function. Missense variants that disrupt the 3'-5' exonuclease (proof-reading) activity of the POLE protein, while not abolishing its polymerase enzyme activity, are associated with an increased risk for colonic adenomatous polyps and colon cancer (PMID: 23263490, 23447401). Loss-of-function variants, which result in an absent or severely disrupted POLE protein, are therefore unlikely to be associated with disease. Without further clinical and genetic evidence, however, this variant has been classified as a Variant of Uncertain Significance. |