Background: In contrast to numerous studies of somatic mutations, the researches of lung cancer germline mutations remain smaller. Some certain germline mutations are assumed to increase susceptibility to lung cancer. However, the details of such mechanism remain to be established. In this study, DNA profiles were performed by targeted next-generation sequencing (NGS). Methods: A retrospective study of 3,421 lung cancer patients with available NGS data was performed to identify germline mutations. Based on the American College of Medical Genetics and Genomics (ACMG) guidelines, germline mutations were categorized as being pathogenic (P), likely pathogenic (LP) and other significance (Non_P). Thus, the patients were divided into two groups: patients with P or LP mutation(P&LP), and patients with Non_P mutation. Results: Of 3421 patients with lung cancer, 174 (5.09%) patients were identified to carry pathogenic or likely pathogenic germline mutations, with a median age of 62.5 years old. BRCA2, ATM, MUTYH, BRCA1 and ERCC2 were the top five genes with germline alterations, and their mutation rates were 11.5, 6.90, 6.32, 5.17 and 4.60%, respectively. Homozygous mutations were identified in only two patients, one was TP53(p.Ser215Ile), and the other was TSC2(splice site alteration). No statistically significant difference in age and sex between P&LP and Non_P group. Somatic mutation data was also involved in our study. The frequency of gene fusion events was same between these two groups. Interestingly, fusion molecular spectrum of P&LP group was different. Among all the 25 fusion events of P&LP group, 20 were unique and 19 fusion events couldn't be retrieved in the PubMed database. In total, 44 genes involved in fusion events and 5 genes were located on chromosome 17. Frequency of FAT1 single nucleotide variant (SNV) mutation was significantly higher in P&LP group (9.77% vs 5.57%, p = 0.03). Most copy number variations (CNV) were amplification, and frequency of EGFR copy number amplification was higher in P&LP group (19.5% vs 12.6%, p = 0.01). Conclusions: These data implied that genomic profile of lung patients who carried germline gene mutations could be different. Associations between germline mutation and lung cancer susceptibility, treatment will be studied further.