POLE
Chr 12ADARDNA polymerase epsilon, catalytic subunit
Also known as: CRCS12, FILS, IMAGEI, POLE1
The protein is the catalytic subunit of DNA polymerase epsilon, which performs chromosomal DNA replication and has 3'-5' proofreading exonuclease activity that corrects replication errors. Mutations cause FILS syndrome (facial dysmorphism, immunodeficiency, livedo, and short stature), IMAGE-I syndrome, and predisposition to colorectal cancer. The gene shows both autosomal dominant and autosomal recessive inheritance patterns and is highly constrained against loss-of-function variants.
Primary Disease Associations & Inheritance
Definitive — sufficient evidence for diagnostic panels
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Typical tolerance to LoF variation
Mild missense constraint
The highest-scoring mechanism for this gene is dominant-negative.
Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.
ClinVar Variant Classifications
300 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 15 | 0 | 11 | 0 | 26 |
Likely Pathogenic | 6 | 0 | 0 | 0 | 6 |
VUS | 3 | 132 | 15 | 3 | 153 |
Likely Benign | 0 | 0 | 66 | 47 | 113 |
Benign | 0 | 0 | 1 | 0 | 1 |
Conflicting | — | 1 | |||
| Total | 24 | 132 | 93 | 50 | 300 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
POLE · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
Chemotherapy Sequential Tislelizumab After Radical Resection in Patients With dMMR/MSI-H or POLE/POLD1 Mutations
NOT YET RECRUITINGA Study to Learn More About How Well Sevabertinib (BAY 2927088) Works and How Safe it is Compared With Standard Treatment, in Participants Who Have Advanced Non-small Cell Lung Cancer (NSCLC) With Mutations of the Human Epidermal Growth Factor Receptor 2 (HER2)
RECRUITINGAn Observational Study of Molecular profIling of Advanced and aggRessive ENdometrial Cancer and 1-st Line Treatment Approaches in Russian Federation
RECRUITINGStudy of the Evolution of the Expression of the LAMP-2 Protein During the Advance in Age
RECRUITINGA Modular Multi-Basket Trial to Improve Personalized Medicine in Cancer Patients (Basket of Baskets)
RECRUITINGTAPUR: Testing the Use of Food and Drug Administration (FDA) Approved Drugs That Target a Specific Abnormality in a Tumor Gene in People With Advanced Stage Cancer
RECRUITINGFamilial Adenomatous Poliposys Italian Network (Rete Italiana Poliposi Adenomatosa Familiare)
ACTIVE NOT RECRUITINGRefining Fertility-sparing Treatment in Endometrial Carcinoma Based on Molecular Classification
RECRUITINGCohort of Tumors With POLE/D1 Mutation
RECRUITINGThe EMPOWER Trial - The Carillon Mitral Contour System® in Treating Heart Failure With at Least Mild FMR
RECRUITINGPrecision Medicine Applied to the Study of Endometrial Cancer: Application of NGS for Molecular Classification
NOT YET RECRUITINGImproving Endometrial Cancer Assessment by Combining Genomic Profiling and Surgical Assessment
RECRUITINGExternal Resources
Links to major genomics databases and tools