ISH-equivocal, as defined by the 2013/2014 ASCO-CAP guidelines13,14 and the recent 2018 update,36 represent approximately 4% to 12% of all breast cancers, or 7000 to 21 000 patients annually.17,18,20,37,38,39,40,41 These cases present patients with breast cancer, oncologists, and pathologists some of their most frequent clinical challenges, because questions remain regarding how HER2 status should be resolved and confusion about HER2-targeted therapies for these patients. The gene discussed is ERBB2; the disease is breast cancer.