In the low-grade HER2 amplification cases (defined as HER2/CEN17 ratio between 2 and 4) a significant HER2 genetic heterogeneity is detected more frequently than breast cancers with a high-grade HER2 amplification (defined as HER2/CEN17 ratio ≥4.0) and HER2 protein overexpression (defined by IHC 3+) (48, 80). The gene discussed is ERBB2; the disease is breast cancer.