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.
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
0 submitted variants 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.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
Pembrolizumab in Treating Participants With Metastatic, Recurrent or Locally Advanced Cancer and Genomic Instability
ACTIVE NOT RECRUITINGCanadian Profiling and Targeted Agent Utilization Trial (CAPTUR)
RECRUITINGKPMNG Study of MOlecular Profiling Guided Therapy Based on Genomic Alterations in Advanced Solid Tumors II
RECRUITINGMRI Radiomics Combined With Pathomics on the Prediction of Molecular Classification and Prognosis of Endometrial Cancer
NOT YET RECRUITINGPrevalence Of Germline Gene Mutations In Patients With Myeloproliferative Neoplasms With Family History
NOT YET RECRUITINGPrecision Medicine Applied to the Study of Endometrial Cancer: Application of NGS for Molecular Classification
NOT YET RECRUITINGStudy of the Evolution of the Expression of the LAMP-2 Protein During the Advance in Age
RECRUITINGGlobal Patient Registry to Monitor Long-term Safety and Effectiveness of Increlex® in Children and Adolescents With Severe Primary Insulin-like Growth Factor-1 Deficiency (SPIGFD).
RECRUITINGAn Intervention to Increase Genetic Testing in Families Who May Share a Gene Mutation Related to Cancer Risk and An Intervention to Help Patients and Their Primary Care Providers Stay Up-to-date About Uncertain Genetic Test Results
RECRUITINGCohort of Tumors With POLE/D1 Mutation
RECRUITINGA Study to Learn More About How Well Sevabertinib 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)
RECRUITINGImproving Endometrial Cancer Assessment by Combining Genomic Profiling and Surgical Assessment
RECRUITINGExternal Resources
Links to major genomics databases and tools