Prevention, diagnosis and clinical management of hereditary breast cancer beyond BRCA1/2 genes

•Hereditary breast cancer is not limited to pathogenic variants in BRCA1/2 but also to the presence of pathogenic variants in other BC-related high, moderate and low penetrance genes.•The clinical management of patients with hereditary BC, particularly those with gPVs in genes other than BRCA1/2, is a complex task. This complexity underscores the urgent need for guidelines based on recent evidence to ensure effective and personalised patient care.•The presence of gPVs in high, moderate, and low penetrance genes can profoundly impact BC prevention, diagnosis, and treatment strategies for patients and their families.•gPVs in BC-related genes could interfere with the response to treatment, determining resistance to some drugs or conversely being targets and predictive biomarkers for agnostic or emerging new BC therapeutic strategies. The detection of germline pathogenic variants (gPVs) in BRCA1/2 and other breast cancer (BC) genes is rising exponentially thanks to the advent of multi-gene panel testing. This promising technology, coupled with the availability of specific therapies for BC BRCA-related, has increased the number of patients eligible for genetic testing. Implementing multi-gene panel testing for hereditary BC screening holds promise to maximise benefits for patients at hereditary risk of BC. These benefits range from prevention programs to antineoplastic-targeted therapies. However, the clinical management of these patients is complex and requires guidelines based on recent evidence. Furthermore, applying multi-gene panel testing into clinical practice increases the detection of variants of uncertain significance (VUSs). This augments the complexity of patients’ clinical management, becoming an unmet need for medical oncologists. This review aims to collect updated evidence on the most common BC-related genes besides BRCA1/2, from their biological role in BC development to their potential impact in tailoring prevention and treatment strategies.