Hereditary Breast and Ovarian Cancer (HBOC) syndrome, most commonly due to pathogenic variants in the BRCA1 and BRCA2 genes, accounts for a significant proportion of familial breast and ovarian cancers.

Carriers of BRCA1 mutations have lifetime risks of up to 72% for breast cancer and 44% for ovarian cancer by age 80. Early identification of mutation carriers allows implementation of surveillance strategies, risk-reducing surgeries, and targeted therapies, such as PARP inhibitors. Familial case series provide insight into clinical heterogeneity, variable penetrance, and challenges in adherence to preventive recommendations. Here, we present a case series of six sisters from a single family with BRCA1-associated cancers, illustrating the spectrum of disease expression and management strategies. 

Case Presentation

Patient Cohort

The family consists of six sisters aged 34–52 years. Four sisters were found to carry a pathogenic BRCA1 frameshift mutation (c.68_69del; p. Glu23ValfsTer17), and two sisters tested negative.

Table 1. Clinical and Genetic Characteristics of the Six Sisters

Figure 3. Pathology of Atefeh, the fourth sister who BRCA‑positive and has undergone prophylactic TAH‑BSO. 

Figure 4. Pathology of the sixth sister with breast cancer and a positive BRCA mutation. 

Pedigree Description

The family pedigree revealed an autosomal dominant inheritance pattern consistent with HBOC. The paternal aunt had early-onset breast cancer at age 30 during pregnancy, followed by ovarian cancer 3-4 years later, and was BRCA-positive. Among the sisters, the proband developed sequential breast and ovarian cancers; one BRCA-positive sister underwent prophylactic TAH-BSO and remains disease-free; two sisters are BRCA-negative and have no malignancy. Pedigree illustrates variable penetrance and expressivity of the BRCA1 mutation.

Genetic Analysis

NGS testing confirmed a heterozygous pathogenic BRCA1 frameshift mutation (NM_007294.4: c.68_69del; p. Glu23ValfsTer17) in four sisters. The mutation was validated via Sanger sequencing. This variant is known to significantly increase susceptibility to breast and ovarian cancers. Cascade genetic testing was performed in available family members to guide surveillance and preventive strategies.

 Discussion

Hereditary Breast and Ovarian Cancer (HBOC) syndrome, most commonly caused by BRCA1 mutations, is associated with variable expressivity and incomplete penetrance. This case series demonstrates heterogeneous clinical manifestations, ranging from prophylactic surgery without malignancy to metachronous breast and ovarian cancers. Early identification of mutation carriers allowed targeted interventions, including surveillance, risk-reducing surgery, and PARP inhibitor therapy, which have shown to improve outcomes. Socioeconomic barriers delayed preventive interventions in some carriers, highlighting the importance of multidisciplinary support. The proband exemplifies dual primary malignancies, emphasizing adherence to NCCN guidelines for risk-reducing strategies and timely genetic counseling.

 Patient Perspective

The sisters shared their perspectives regarding genetic testing, cancer diagnosis, and preventive strategies. The proband, Asieh, emphasized her commitment to completing surveillance and maintenance therapy with olaparib after dual breast and ovarian cancers. Parvaneh expressed her intention to undergo a risk-reducing mastectomy. Atefeh highlighted financial constraints delaying her prophylactic breast surgery, while she maintains regular breast surveillance. Elham reported relief after completing breast surgery and chemotherapy but expressed concern regarding the evaluation and management of her ovaries. Maryam and Zahra, both BRCA-negative, valued genetic testing and continued regular monitoring. Collectively, the sisters underscored the importance of early genetic counseling, informed decision-making, and family support in managing hereditary cancer risk.

Figure 6. Histopathologic section of ovarian serous carcinoma (proband sister) showing complex papillary architecture with marked nuclear atypia and high mitotic activity (Hematoxylin and Eosin stain).