Variantes patógenas de la línea germinal POLE en el dominio de la exonucleasa (lección de prueba) causan polimeras...
Vista determinista de la entidad fuente YAML. La autoridad clínica sigue con los ID de fuente citados y estado de firma del revisor.
| ID | BMA-POLE-GERMLINE-POLYMERASE-PROOFREADING |
|---|---|
| Tipo | Relevancia terapéutica |
| Situación | reviewed 2026-05-18 | pending_clinical_signoff | actionability review required |
| Enfermedades | DIS-CRC |
| Fuentes | SRC-NCCN-GENETIC-FAMILIAL-CRC-2025 |
Hechos relativos a la posibilidad de adoptar medidas
| Biomarcador | BIO-POLE-GERMLINE |
|---|---|
| Variante | POLE germline exonuclease-domain pathogenic (PPAP — polymerase proofreading–associated polyposis) |
| Enfermedad | DIS-CRC |
| El nivel de ESCAT | IIA |
| Combinaciones recomendadas | colonoscopy q1-2y starting age 20-25 with polypectomy, EGD q3y from age 30, endometrial sampling + TVUS q1-2y from age 30-35 (women), annual urinalysis from age 30, for POLE-mutant advanced CRC / endometrial: pembrolizumab 200 mg q3w — high response rate in ultramutator setting (NCCN Category 1 for TMB-H or MSI-H), cascade testing to first-degree relatives; specific to exonuclease-domain variants (Pro286Arg, Val411Leu most common) |
| Resumen de las pruebas | POLE germline pathogenic variants in the exonuclease (proofreading) domain cause polymerase proofreading–associated polyposis (PPAP) — characterized by attenuated/oligo-polyposis (typically <100 adenomas), early-onset colorectal cancer, elevated endometrial cancer risk in women, and characteristic ultramutator tumor phenotype (TMB >100 mut/Mb) with potential immunotherapy responsiveness. Confirmed-carrier surveillance protocol (Lynch-like; per NCCN Genetic/Familial CRC 2025): colonoscopy q1-2y starting age 20-25, EGD q3y from age 30, endometrial sampling + TVUS q1-2y from age 30-35 in women, urinalysis annual from 30 (overlap with Lynch organ spectrum). The ultramutator phenotype in POLE-mutant tumors predicts immunotherapy benefit (high TMB) — pembrolizumab is FDA- approved for TMB-high (≥10 mut/Mb) advanced solid tumors regardless of tissue; POLE-mutant CRC and endometrial benefit appears substantial in small series. ESCAT IIA (predisposition + tumor-phenotype actionability). |
Notas
STUB — Wave A+B germline expansion. Linked Indication: IND-LYNCH-CARRIER- SURVEILLANCE used as closest-fit (POLE-specific Indication does not yet exist; PPAP overlaps Lynch surveillance for CRC + endometrial). Note that IND-ENDOMETRIAL-STAGE-I-POLE-OBSERVATION exists for the somatic-POLE endometrial-treatment context — distinct from germline-carrier surveillance handled here. Two-Clinical-Co-Lead signoff queued. Variant classification matters: only exonuclease-domain variants (Pro286Arg, Val411Leu, Ser297Phe) drive PPAP — non-exonuclease variants are usually uncertain significance.
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