To evaluate the role of germline mutations of TP53 gene among a Chinese population with high risk for breast cancer.A total of 81 BRCA-negative breast cancer probands from cancer families were analyzed using targeted capture and next-generation sequencing. Candidate mutations were verified with Sanger sequencing. Co-segregation analyses were carried out to explore the likely pathogenicity of the mutation.Of the 81 BRCA-negative patients, 3 exonic mutations in the TP53 gene were identified in 3 breast cancer patients. Of these, 2 mutations were previously reported and 1 was novel. One family with TP53 mutation has met the criteria for Li-Fraumeni syndrome (LFS) and accounted for 9.1% of all families who fulfilled the diagnostic criteria for LFS. Two of the carriers were diagnosed with breast cancer under the age of 30, and have accounted for 11.8% (2/17) of all very young (≤30 years) breast cancer patients in our study.The TP53 germline mutation is more common in Chinese population with a high risk for breast cancer than previously thought. TP53 gene mutation screening should be considered particularly for patients with a family history of LFS and very young age of onset.