BackgroundBreast cancer is a leading cause of morbidity and mortality in women worldwide. At King Hussein Cancer Center (KHCC), Amman, Jordan, 38% of breast cancer diagnoses are in women younger than 45 years, which might reflect a high prevalence of hereditary breast cancer. The aim of this study was to assess the contribution of germline mutations in BRCA1 and BRCA2 to breast cancer treated at KHCC. We also describe our experience in dealing with this delicate cultural issue in a tribal-based country with Palestinian–Jordanian family origins. MethodsPatients treated at KHCC with stage I–IV breast cancer, with a high-risk profile according to US National Comprehensive Cancer Network guidelines, were invited to participate. Patients were interviewed for consent and had full autonomy to decide whether they wanted to know their test result, inform their treating physician, or have a copy of the result placed in their charts. Charts were reviewed for clinical data and tumour pathology. A 10 mL blood sample was obtained for DNA extraction. A detailed three-generation family history was obtained. BRCA sequencing was done at the Myriad Genetics laboratory using BRCAnalysis. BRCA mutations were classified as deleterious, suspected deleterious, variant of uncertain significance (VUS), or favour polymorphism (harmless). The report received for each mutation result contained a detailed description of level of risk associated with the involved variant and estimated lifetime risk of breast and ovarian cancer, risk of second breast cancer or subsequent ovarian cancer, and risk of cancer to first, second, and third-degree family members. Patients were invited to an ad-hoc clinic with the treating physician for disclosure of results and counselling about estimated cancer risk to patient and relatives. Interviews with patients were summarised as text and qualitiative analysis for common themes was done. Challenges encountered during patient consent and disclosure of results were documented, as well as proposed solutions. Ethical approval was granted by the KHCC Institutional Review Board (no 11 KHCC 63). FindingsThe first 102 patients to meet inclusion criteria were invited to participate in the study, of whom 100 enrolled and provided written informed consent. Two patients declined to participate (a response rate of 98%). Six participants were residents of the West Bank and treated at KHCC, and 66 were from families of Palestinian origin residing in Jordan. The remaining patients were Jordanians. Median age was 40 years (range 22–75). 20 patients had deleterious mutations and seven had suspected deleterious mutations in BRCA1 and BRCA2 genes. Seven VUS were detected. All patients with BRCA1 and BRCA2 mutations had a significant family history of breast or ovarian cancer. Nevertheless, many patients with a significant family history (62 of 100) tested negative for BRCA1 and BRCA2 mutations. Many ethical dilemmas were highlighted during patient encounters, mainly relating to the guarantee of confidentiality and privacy in a tribal-based culture, fears of false reassurance, autonomy versus beneficence, and the bounds of physician–patient confidentiality when relatives are at genetic risk of cancer. Potential insurance, employment, and social discrimination implications were also addressed with the patients before testing and in more detail after disclosure of positive mutation results, which flagged a legal void in local genetic testing and data protection regulations. InterpretationOur cohort showed an important incidence of deleterious and suspected deleterious BRCA1 and BRCA2 mutations, suggesting that genetic testing should be discussed and offered to patients with high-risk features. Many high-risk patients tested negative for BRCA1 and BRCA2 mutations, therefore future studies should aim to test for mutations in other breast cancer susceptibility genes (eg, CHEK2, PALB2, and BRIP1). Running culturally sensitive genetic research in a country with limited resources is a challenging exercise and highlights the urgent need for guiding regulations. We recommend establishing a clinical cancer genetics programme, through which unaffected family members would benefit from early breast cancer screening and appropriate risk-reduction measures. FundingSister Institution Network Fund of MD Anderson Cancer Center and KHCC.