Unlike the prototypical HER2 gene amplifications that define a major subset of primary breast cancer and are highly correlated with response to HER2-targeting antibodies, point mutations in HER2 are less well characterized, and their occurrence within multiple domains of the receptor, including extracellular, catalytic, and cytoplasmic tail, make them less readily interpretable than recurrent kinase domain mutations, such as observed in the related receptor EGFR.29 The gene discussed is ERBB2; the disease is breast cancer.