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. 2025 Apr;210(3):507-519.
doi: 10.1007/s10549-025-07643-4. Epub 2025 Feb 24.

Considerations for hereditary breast and ovarian cancer syndrome molecular diagnosis: experience from the clinical practice

Miriam Potrony  1   2 , Blai Morales-Romero  1   2 , Lorena Moreno  3 , Belen Pastor  3   4   5 , Elia Grau  3 , Celia Badenas  1   2 , José Luis Villanueva-Cañas  6 , Aina Montalbán-Casafont  6 , Coral Arnau-Collell  3 , Teresa Ramon Y Cajal  4 , Isabel Aragón Manrique  7 , Pilar Carrasco Salas  8 , Susana Puig  2   9 , Paula Aguilera  2   9 , Inmaculada Alonso  10 , Isaac Cebrecos  10 , Eduardo González-Bosquet  10 , Begoña Mellado  11 , Laura Ferrer-Mileo  4 , Adela Rodriguez-Hernandez  4   5   12 , Aleix Prat  4   5   12 , Montserrat Muñoz  4   5   12 , Lydia Gaba  4   5   12 , Barbara Adamo  4   5   12 , Josep Oriola  1 , Aurora Sánchez  1   2 , Joan Anton Puig-Butillé  13   14   15
Affiliations

Considerations for hereditary breast and ovarian cancer syndrome molecular diagnosis: experience from the clinical practice

Miriam Potrony et al. Breast Cancer Res Treat. 2025 Apr.

Abstract

Purpose: The implementation of the next-generation sequencing (NGS) in clinical practice has improved the genetic diagnosis of Hereditary Breast and Ovarian Cancer Syndrome (HBOC). We aimed to evaluate the diagnostic outcomes of using an NGS cancer gene panel in clinical practice for patients selected based on personal and/or family history of breast, ovarian, prostate, melanoma, and other HBOC-associated cancers.

Methods: The study series included 2561 consecutive Spanish individuals referred for genetic testing, comprising 2445 cancer patients and 116 healthy individuals with family history of HBOC. Eleven HBOC susceptibility genes (BRCA1, BRCA2, PALB2, ATM, CHEK2, BARD1, BRIP1, RAD51C, RAD51D, TP53, and PTEN) and three Lynch Syndrome genes (MLH1, MSH2, and MSH6) available for opportunistic testing were analyzed using a commercial Hereditary Cancer Panel and an in-house bioinformatics pipeline.

Results: Overall, the diagnostic yield was 11.0% in cancer patients and 8.6% in healthy individuals with a family history of breast/ovarian cancer. Pathogenic variants in high-risk genes were more frequent in patients with multiple HBOC tumors and a family history of different HBOC cancers. Additionally, we diagnosed five families with Lynch syndrome through opportunistic testing.

Conclusion: Testing cancer susceptibility genes using an agnostic strategy confers a diagnostic benefit for hereditary cancer syndromes compared to phenotype-driven test, without adding complexity to the study. The analysis of healthy individuals with a family history of HBOC detects pathogenic variants in a cost-efficient percentage of cases, resulting in a good alternative strategy when the index case is unavailable.

Keywords: Breast cancer; Genetic counseling; Genetics; Hereditary cancer; NGS; Variants.

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Conflict of interest statement

Declarations. Competing interests: The authors declare no competing interests.

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