Genetic tumor syndromes in female cancer: insights into inherited cancer predisposition and clinical implications

A relevant proportion of malignancies predominantly or exclusively affecting women, including breast and gynecologic cancers, is attributable to hereditary tumor syndromes, profoundly impacting cancer risk, prognosis, and therapeutic management. Today, the routine use of comprehensive germline panels has shifted the focus from solely pathogenic BRCA1/2 variants to include numerous pathogenic variants of other high- and moderate-risk genes. A broad spectrum of genetic alterations has been identified as causative for Hereditary Breast and Ovarian Cancer syndrome (HBOC), encompassing not only BRCA1 and BRCA2, but also PALB2, ATM, BARD1, CHEK2, BRIP1, RAD51C, and RAD51D. Beyond HBOC, numerous additional hereditary tumor syndromes are of significance in senologic and/or gynecologic oncology, including Li-Fraumeni syndrome, Lynch syndrome, DICER1 syndrome, Hereditary Diffuse Gastric Cancer, Neurofibromatosis type 1, Peutz-Jeghers syndrome, PTEN hamartoma tumor syndrome, Tuberous Sclerosis, and pathogenic variants in NBN and SMARCA4. Affected individuals are offered specialized surveillance to enable early detection or even prevention of cancer. In addition to regular clinical examinations and imaging, preventive strategies may include risk-reducing surgery. Pathogenic germline variants also influence therapeutic management of cancer patients. For specific indications, targeted therapies are available, for example PARP [poly (ADP-ribose) polymerase] inhibitors for pathogenic BRCA variant carriers across multiple tumor entities. Optimal management requires interdisciplinary coordination, encompassing genetic counseling, early detection, and risk-reducing strategies within specialized centers. This review provides a comprehensive overview of hereditary tumor syndromes predisposing to breast and gynecologic malignancies, with a focus on genetic basis, associated cancer risks, and implications for clinical management. By delineating these syndromes, it aims to assist clinicians in recognizing hereditary cancer predisposition and in guiding affected individuals within routine senologic and gynecologic practice.