Patients with CYP2A6 deletion exhibited a lower tumor mutation burden (TMB) than those with normal CYP2A6. There was no increase in TMB in tumors other than lung cancer in smokers, even when germline CYP2A6 was retained, indicating that the identified germline hybrids affect mutation accumulation in lung cancer in patients with a history of smoking. Here, CYP2A6 is linked to lung cancer.