Moderate-risk variants in hereditary breast and ovarian cancer: seven-year experience from a specialized center

Moderate-risk gene variants represent an increasingly recognized component of hereditary breast and ovarian cancer (HBOC) predisposition, yet their clinical interpretation and management remain less standardized than those of high-penetrance genes. This study provides a seven-year real-world evaluation of genetic variants in ATM, BARD1, CHEK2, RAD51C, and RAD51D in individuals undergoing germline testing at a specialized HBOC center, with a particular focus on variant distribution and associated clinical management. We retrospectively analyzed germline testing data from 3416 individuals evaluated at the HBOC center Erlangen between 2018 and 2024. Testing indications included predictive as well as diagnostic and therapeutic testing in the context of breast and gynecologic neoplasms. Variant classifications followed ACMG/IARC (American College of Medical Genetics and Genomics/ International Agency for Research on Cancer) criteria. Clinical recommendations, including participation in the intensified breast cancer surveillance (IBCS) program and risk-reducing surgery, were extracted from structured counseling documentation. (Likely) Pathogenic variants in moderate-risk genes were identified across all clinical subgroups. CHEK2 represented the most frequently altered moderate-risk gene, followed by ATM. In contrast, (likely) pathogenic variants in BARD1, RAD51C, and RAD51D were observed solely among individuals undergoing predictive testing or presenting with breast malignancies. A small subset of individuals carried more than one (likely) pathogenic variant in HBOC susceptibility genes. Most women with moderate-risk variants were enrolled in the IBCS program, although in justified cases participation was withheld based on patient-specific risk factors. An isolated moderate-risk variant generally did not warrant a recommendation for risk-reducing breast surgery. Risk-reducing salpingo-oophorectomy (RRSO) was primarily discussed with individuals harboring RAD51C or RAD51D variants. Individualized modifications to the recommendations were applied especially in cases with complex genotypes comprising multiple (likely) pathogenic variants. In conclusion, this study demonstrates considerable heterogeneity in germline variants among individuals evaluated for HBOC susceptibility and highlights the particular challenges associated with interpreting moderate-risk gene alterations. The findings underscore the importance of individualized clinical assessment and support the use of real-world data to inform evidence-based surveillance and prevention strategies in hereditary cancer care.