Observed missense mutations are enriched in the EGF2, EGF4, EGF8, EGF9, EGF10, EGF11, EGF12, EGF29, EGF31, RAM, and ANK1 domains in HNSCC, suggesting that mutations in these regions are likely to inactivate NOTCH1 signaling. The gene discussed is NOTCH1; the disease is head and neck squamous cell carcinoma.