In this study, we leveraged a cohort of more than 8,000 breast cancer patients whose cancers were subjected to multigene panel sequencing using the FDA-authorized Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) to identify the spectrum of ESR1 mutations whose location and impact rendered them unlikely to simply mimic the immediate ligand-induced changes in the ligand-binding pocket. The gene discussed is ESR1; the disease is cancer.