Certain types of primary tumor, particularly triple primary tumors with germline mutations, are rare. The present study reports a novel case of the metachronous occurrence of three pathological conditions, namely, non-small-cell lung cancer (NSCLC), early T cell precursor acute lymphoblastic leukemia (ETP-ALL) and SCLC. The present study used next-generation sequencing to aid diagnosis. A 44-year-old male patient presented to The First Affiliated Hospital Zhejiang University School of Medicine (Hangzhou, China) in September 2016.) with a nodule in the right lower lung during an annual checkup. Then, the patient was diagnosed with poorly differentiated NSCLC (T1N2M0; stage IIIA) and underwent surgical resection and biopsy. In September 2018, the patient was diagnosed with ETP-ALL with superficial lymphadenopathy. Germline testing demonstrated germ cell variants of ERCC excision repair 6, chromatin remodeling factor (ERCC6; c.1322A>G) and LYL1 basic helix-loop-helix family member (LYL1; c.587T>A). In November 2020, the patient was diagnosed with SCLC by bronchoscopic biopsy following allogeneic hematopoietic stem cell transplantation. The patient was diagnosed with lung cancer in October 2016 and the treatment were: surgery, chemotherapy, radiotherapy, and targeted therapy. In October 2018, the patient was diagnosed with ETP-ALL and the treatment were: chemotherapy and allogeneic hematopoietic stem cell transplantation. In November 2020, the patient was diagnosed with small cell lung cancer and received chemotherapy and radiotherapy. The patient died at September 2022. The present case highlighted the importance of monitoring germline mutations in patients and their families to facilitate early diagnosis, appropriate treatment and prognostic evolution in the face of rapid recurrent cancer. [ABSTRACT FROM AUTHOR]