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Approximately 10% of breast cancers are associated with the inheritance of a pathogenic variant (PV) in one of the breast cancer susceptibility genes. Multiple breast cancer predisposing genes, including TP53, are responsible for the increased breast cancer risk. Tumor protein-53 (TP53) germline PVs are associated with Li-Fraumeni syndrome, a rare autosomal dominant inherited cancer predisposition syndrome associated with early-onset pediatric and multiple primary cancers such as soft tissue and bone sarcomas, breast cancer, brain tumors, adrenocortical carcinomas and leukemias. Women harboring a TP53 PV carry a lifetime risk of developing breast cancer of 80-90%. The aim of the present narrative review is to provide a comprehensive overview of the criteria for offering TP53 testing, prevalence of TP53 carriers among patients with breast cancer, and what is known about its prognostic and therapeutic implications. A summary of the current indications of secondary cancer surveillance and survivorship issues are also provided. Finally, the spectrum of TP53 alteration and testing is discussed. The optimal strategies for the treatment of breast cancer in patients harboring TP53 PVs poses certain challenges. Current guidelines favor the option of performing mastectomy rather than lumpectomy to avoid adjuvant radiotherapy and subsequent risk of radiation-induced second primary malignancies, with careful consideration of radiation when indicated post-mastectomy. Some studies suggest that patients with breast cancer and germline TP53 PV might have worse survival outcomes compared to patients with breast cancer and wild type germline TP53 status. Annual breast magnetic resonance imaging (MRI) and whole-body MRI are recommended as secondary prevention., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ‘Eva Blondeaux reports research grant (to the Institution) from Gilead to pursue research effort in the field of TP53 pathogenic variants. Kevin Punie reports honoraria for consultancy/advisory roles from Astra Zeneca, Eli Lilly, Exact Sciences, Focus Patient, Gilead Sciences, MSD, Novartis, Pfizer, Roche, Seagen; honoraria for consultancy/advisory roles paid to my institution from Astra Zeneca, Eli Lilly, Exact Sciences, Gilead, MSD, Novartis, Pfizer, Roche, Seagen. Research funding paid to my institution from Sanofi and MSD. Stock options: Need Inc. Travel support: Astra Zeneca, Novartis, Pfizer, PharmaMar, Roche. Carmine De Angelis reports advisory role for Roche, Lilly, Novartis, Astrazeneca, Pfizer, Seagen, Gilead, and GSK and speaker honoraria from Roche, Lilly, Novartis, Pfizer, Seagen, and GSK, Travel Grants from Gilead and research support (to the Institution) from Novartis outside the submitted work. Sabine C. Linn reports an advisory role for AstraZeneca and Daiichi Sankyo Europe GmbH (paid to the institution), travel and accommodation expenses from Daiichi Sankyo Europe GmbH, and research support (to the institution) from Genentech/Roche, AstraZeneca, Bristol Myers Squibb, Tesaro (now GSK), Merck, Immunomedics (now Gilead), Eurocept Pharmaceuticals, Agendia, and Novartis. Mara Cruellas reports speaker honoraria from Roche and Astrazeneca. Shani Paluch-Shimon reports - advisory Board consultancy, speaker’s bureau: AstraZeneca, Pfizer, Novartis, Lilly, Roche, MSD, Exact Sciences. Gilead. Travel: Roche. Research Funding: Pfizer. Matteo Lambertini reports advisory role for Roche, Lilly, Novartis, Astrazeneca, Pfizer, Seagen, Gilead, MSD and Exact Sciences and speaker honoraria from Roche, Lilly, Novartis, Pfizer, Sandoz, Libbs, Daiichi Sankyo and Takeda, Travel Grants from Gilead and research support (to the Institution) from Gilead outside the submitted work. All the other authors declare no conflict of interest.’, (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)