Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are present in approximately 80% of the lung adenocarcinomas that respond to first and second generation EGFR tyrosine kinase inhibitors (TKIs, eg, gefitinib, erlotinib and afatinib). Two types of mutations account for approximately 80-90% of all EGFR mutations: short in-frame deletions in Exon 19 and a point mutation in exon 21 at codon 858 (L858R). Other less common mutations in exons 18, 20, and 21 are found in 10-20% of EGFR-mutated cases. Exon 20 mutations are more commonly associated with resistance to tyrosine kinase inhibitors (TKIs), but may respond to third generation TKI (eg, osimertinib). This EGFR variant (G796S) lies within the tyrosine kinase domain and has been reported in rare cases of lung adenocarcinomas, squamous cell carcinoma of head and neck and prostate adenocarcinoma. In silico studies suggest G796S mutation may confer resistance to TKIs. However, additional studies are needed to further elucidate the oncogenicity of the mutation and therapeutic implications of this rare variant.