What question did this study set out to answer?

This study aims to evaluate how family history influences the likelihood of finding pathogenic variants in HBOC genetic testing.

May 29, 2026

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

Key Points

This study aims to evaluate how family history influences the likelihood of finding pathogenic variants in HBOC genetic testing.
Retrospective analysis of 62 patients suspected of HBOC with inclusion criteria based on cancer diagnosis age or family history.
Used a 28-gene HBOC multigene panel for genetic testing, classifying variants per ACMG/AMP guidelines.
In the 'young without family history' group, 9.75% had pathogenic variants; 34.1% had variants of uncertain significance.
In contrast, 71.42% of patients with a family history had pathogenic variants, primarily in BRCA1 and BRCA2.
The study indicates a higher prevalence of clinically actionable variants in patients with documented family histories.

Abstract

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.

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