Abstract Inherited lung cancer risk, particularly in non-smokers, is poorly understood. Genomic and ancestry analysis of 1,153 lung cancers from Latin America revealed striking associations between Native American ancestry and their somatic landscape, including tumor mutational burden (TMB), and specific driver mutations in EGFR, KRAS , and STK11 . A local Native American ancestry risk score predicted EGFR and KRAS mutation frequency more strongly than global ancestry, suggesting that germline genetics (rather than environmental exposure) underlie these disparities. Significance The frequency of somatic EGFR and KRAS mutations in lung cancer varies by ethnicity but we do not understand why. Our study suggests that the variation in EGFR and KRAS is directly associated with genetic ancestry and suggests further studies to identify germline alleles that underpin this association.