The importance of family history in indicating HBOC genetic testing in a resource-limited setting.

e12582 Background: Genetic screening for hereditary breast and ovarian cancer (HBOC) is guided by clinical criteria such as early-onset disease and family history. In resource-limited settings with restricted access to next-generation sequencing (NGS), optimizing patient selection is essential to maximize diagnostic yield. This study evaluates the predictive value of these criteria by comparing the distribution of pathogenic/likely pathogenic variants and variants of uncertain significance (VUS) between early-onset patients without family history and those with a documented family history of breast and/or ovarian cancer. Methods: We retrospectively analyzed 62 patients referred for suspected HBOC who met at least one inclusion criterion: breast or ovarian cancer diagnosed before age 40 and/or a positive family history. Genetic testing was performed using an extended 28-gene HBOC multigene panel. Variants were classified according to ACMG/AMP guidelines. Results: Among the 41 patients in the “young without family history” group, pathogenic or likely pathogenic variants were identified in 4 individuals (9.75%), involving BRCA1 (n = 2), ATM (n = 1), and MUTYH (n = 1). Variants of uncertain significance were detected in 14 patients (34.1%), affecting ATM , BRCA1 , RAD50 , MRE11A , NBN , CDKN2A , MLH1 , MUTYH , and CDH1 .In contrast, among the 21 patients with a documented family history of breast and/or ovarian cancer, pathogenic or likely pathogenic variants were identified in 15 patients (71.42%), predominantly involving high-penetrance genes, namely BRCA1 (n = 7) and BRCA2 (n = 6), with additional variants in ATM (n = 1) and MUTYH (n = 1). VUS were identified in 6 patients (28.5%), affecting ATM , NBN , CHEK2 , APC , and NF1 . Overall, VUS were relatively more frequent in the early-onset group, whereas patients with family history showed a markedly higher yield of clinically actionable pathogenic variants. Conclusions: Family history is a substantially stronger predictor of pathogenic variants than young age at diagnosis alone in HBOC genetic screening. In resource-limited settings, prioritizing testing based on family history may optimize the use of NGS and improve identification of high-risk individuals. The higher burden of VUS observed in early-onset patients without family history should be viewed not as a limitation of testing, but as a key challenge in understanding cancer susceptibility in young individuals lacking pathogenic variants in high-penetrance genes, raising questions about the role of moderate-penetrance genes, polygenic risk, and regulatory or non-genetic factors.