For advanced non-small cell lung cancer (NSCLC) patients with common epidermal growth factor receptor (EGFR) mutations (exon 19 deletions or the exon 21 L858R mutation), tyrosine kinase inhibitors (TKIs) are the standard therapies. However, EGFR germline mutations are extremely rare in lung cancer, and the effective therapy is unclear. This study reports a patient with primary breast and lung cancer carried rare germline EGFR R776H and somatic L861Q mutation, who benefit from EGFR TKIs. Her family cancer history review demonstrated that her three out of four sisters with lung cancer were positive for EGFR R776H. Interestingly, only her healthy sister had type O blood, different from other sisters with type B blood. Our study provides a meaningful insight into the potential treatment option for patients with germline EGFR R776H and somatic L861Q mutation and highlights the importance of next-generation sequencing (NGS) in discovering rare genetic alterations to guide the prevention of genetic disease.