From February 2013 to December 31, 2021, twenty-nine patients with stage IV disease harboring somatic ERBB2 oncogenic variants were identified through the CoPPO Program of whom nineteen commenced HER2-targeted therapy including breast cancer (n = 8), urothelial carcinoma (n = 3), non-small cell lung cancer (n = 3), and one case each of cervical cancer, cholangiocarcinoma, gastroesophageal junction cancer, germ cell tumor, and extramammary Paget’s disease (Fig. 1). The gene discussed is ERBB2; the disease is breast carcinoma.