NTHL1 germline biallelic (homozygous or compound heterozygous) pathogenic variants cause...
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| ID | BMA-NTHL1-GERMLINE-NAP-BIALLELIC |
|---|---|
| Type | Pertinence thérapeutique |
| État | reviewed 2026-05-18 | pending_clinical_signoff | actionability review required |
| Maladies | DIS-CRC |
| Sources | SRC-NCCN-GENETIC-FAMILIAL-CRC-2025 |
Faits relatifs à l ' action en justice
| Biomarqueur | BIO-NTHL1-GERMLINE |
|---|---|
| Variante | NTHL1 géroïde biallélique pathogène (polypose associée à la NTHL1, NAP) |
| Maladie | DIS-CRC |
| Niveau ESCAT | IIA |
| Combinaisons recommandées | colonoscopy q1-2y from age 25-30 with polypectomy, EGD q3-5y from age 30, breast MRI + mammography annual from age 30-35 (women), endometrial sampling + TVUS q1-2y from age 35-40, annual urinalysis + skin exam, cascade testing — partner carrier screening for couples planning children (autosomal-recessive transmission) |
| Résumé des faits | NTHL1 germline biallelic (homozygous or compound heterozygous) pathogenic variants cause NTHL1-associated polyposis (NAP) — autosomal-recessive, attenuated/oligo-polyposis with early-onset colorectal cancer plus a broad multi-tumor spectrum: breast (~60% lifetime in women), endometrial, duodenal, urothelial, brain tumors, basal-cell carcinomas, and hematologic malignancies. Tumors carry the characteristic NTHL1 mutational signature (SBS30 — C>T at NCG and NCT contexts) from defective base-excision repair. Confirmed-carrier (biallelic) surveillance protocol (per Grolleman et al. 2019 / NCCN Genetic CRC): colonoscopy q1-2y from age 25-30 with polypectomy, EGD q3-5y from age 30, breast MRI + mammography annual from age 30-35 (women), endometrial sampling + TVUS q1-2y from 35-40, urinalysis annual, skin exam annual. Heterozygous (monoallelic) NTHL1 carriers are not currently considered at materially elevated cancer risk and do not enter surveillance — only biallelic carriers qualify. ESCAT IIA. |
Notes
STUB — Wave A+B germline expansion. Linked Indication: IND-LYNCH-CARRIER- SURVEILLANCE used as closest-fit multi-organ surveillance template (no NAP-specific Indication exists yet). Two-Clinical-Co-Lead signoff queued. Critical: only biallelic NTHL1 carriers enter this protocol; monoallelic heterozygotes do not (autosomal-recessive). Partner-carrier testing for cascade reproductive counseling. Tumor mutational signature SBS30 in a CRC without explicit germline result is a strong NTHL1 case-finding signal.
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