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Epidermal growth factor receptor gene (EGFR) mutations are relatively common oncogenic drivers in non–small cell lung cancer (NSCLC). The outcomes of patients who present with less common EGFR mutations or more than one EGFR mutation are uncertain. We reviewed our experience with the S768I mutation of exon 20 of EGFR to provide insight into the clinical significance of this mutation.We used a natural language search program to search our electronic medical record system and every EGFR mutation analysis of patients with NSCLC treated at Mayo Clinic that was performed in our Department of Molecular Genetics to identify patients with EGFR S768I mutation. Relevant clinical and laboratory data were abstracted for selected cases, including evaluation of response after treatment with tyrosine kinase inhibitors.A total of 1527 patients with NSCLC who underwent EGFR testing were reviewed. The S768I mutation was present in nine patients (0.59%), four of whom were female. Only three had an isolated S768I mutation, four had a concurrent G719 mutation, and two had a concurrent L858R mutation. Among patients with stage IV disease treated with erlotinib (n = 4), one had an isolated S768I mutation and three had additional mutations (two patients with G719 and one patient with L858R). The tumor response to erlotinib of patients with stage IV disease was highly variable (progression-free survival ranged from 3 to 30 months and overall survival ranged from 5 to more than 51 months).S768I mutations in exon 20 of the EGFR gene are rare and are typically seen in conjunction with sensitizing EGFR mutations. Because of this mutation's rarity and the variability of responses of treated cases, its exact prognostic and predictive role is not fully understood. In our experience, S768I mutations in isolation do not necessarily confer sensitivity to erlotinib, but in conjunction with sensitizing EGFR mutations, S768I mutations do not restrict efficacy.