To explore the relationship between germline rare variants of bromodomain and extraterminal domain (BET) protein family-encoding genes and susceptibility to cancer in some regions of China. Capturing probes were designed for bromodomain-containing protein 2 (BRD2), BRD3 and BRD4 genes, and Illumina high-throughput sequencing platform was used to conduct targeted sequencing of genomic DNA of peripheral blood leukocytes from 1 673 patients with cancer and 1 661 individuals without cancer recruited between October 2015 and July 2018 from Chinese PLA General Hospital, the Second Affiliated Hospital of Guangxi Medical University, People's Hospital of Macheng City, Hubei Province and Geneplus-Beijing Co. Ltd. Mutation detection and analysis were carried out according to the genome analysis toolkit (GATK) best practice guidelines, ANNOVAR and VEP software were used for annotation, and germline rare variants in BET family were screened. To determine potential pathogenic germline rare variants, clinical and experimental evidence was obtained from the ClinVar database and SIFT and Polyphen-2 softwares were used to predict pathogenicity. Fisher's exact test was used to compare the difference of the carrying rate of variants in the case group and the control group, and multivariate regression analysis was performed with the SKAT software with sex and age used as covariates. Among the 1 673 cancer patients, 911 were males and 762 were females, with the mean age was (57.9±11.7) years. There were 1, 111 cases (66.4%) of lung cancer, 266 cases (15.9%) of colorectal cancer, 186 cases of breast cancer (11.1%), and 110 cases (6.6%) of esophagus or gastric cancer. In the same period 1, 661 non-tumor control individuals were recruited, including 821 males and 840 females, with the mean age was (44.5±13.9) years. It was observed that there were 4 potential pathogenic germline rare variants in BRD2 gene carried by 17 patients with cancer, 5 potential pathogenic germline rare variants in BRD3 gene and 8 potential pathogenic germline rare variants in BRD4 gene. The carrying rate of potential pathogenic germline rare variants in BRD2 gene in cancer patients was 1.02% (17/1 673), significantly higher than that in controls without cancer [0 (0/1 661); =+∞, 95%: 4.81-+∞, <0.001]. The carrying rate of potential pathogenic germline rare variants in BRD3 gene in cancer patients was 0.24% (4/1 673), and the difference was not statistically significant compared with controls without cancer [0.12% (2/1 661); =1.99, 95%: 0.46-10.47, =0.690]. The carrying rate of potential pathogenic germline rare variants in BRD4 gene in cancer patients was 0.18% (3/1 673), and the difference was not statistically significant compared with controls without cancer [0.36% (6/1 661); =0.50, 95%: 0.14-2.08, =0.340]. Furthermore, the dataset of whole exome sequencing of Chinese individuals in "Huabiao Project" was used as an additional control, and the rate of carrying BRD2 rare variants in cancer patients was 17/3 346 (0.51%), significantly higher than that in controls without cancer [0.07% (3/4 154); =7.07, 95%: 2.32-22.83, <0.001]. Among the 17 patients carrying 4 potentially pathogenic germline rare variants of BRD2 gene, 9 were patients with lung cancer, 6 were patients with colorectal cancer, 1 was patient with breast cancer, and 1 was patients with esophagus or gastric cancer. The carrying rate of potential pathogenic germline rare variants in BRD2 gene in lung cancer patients was 0.81 (9/1 111), significantly higher than that in controls without cancer [0(0/1 661); =+∞, 95%: 3.95-+∞,<0.001]. The carrying rate of potential pathogenic germline rare variants in BRD2 gene in patients with colorectal cancer was 2.26% (6/266), significantly higher than that in controls without cancer [0(0/1 661); =+∞, 95%: 9.03-+∞, <0.001]. Wilcoxon rank-sum test results showed that patients with colorectal cancer carrying BRD2 rare variants had an earlier age at diagnosis [(47.0±7.4) vs (57.2±12.1) years old, =0.017]. BRD2 gene may be served as a candidate genetic susceptibility gene for lung cancer and colorectal cancer. Carrying BRD2 potential pathogenic germline rare variants is associated with higher risk of lung cancer and colorectal cancer, and with earlier age of colorectal cancer.