Early-onset high-risk prostate adenocarcinoma in a germline BRCA2 pathogenic variant carrier––clinical management and familial implications: a case report

Germline pathogenic variants in DNA damage repair genes, particularly BRCA2, are associated with an increased risk of aggressive prostate cancer and have important implications for genetic counseling and familial risk assessment. Current guidelines support germline testing in men with high-risk or early-onset disease and a suggestive family history. A 43-year-old Iranian man presented with urinary frequency, nocturia, and unintentional weight loss. His serum PSA was 38 ng/mL. Multiparametric MRI showed a large PI-RADS 5 lesion with seminal vesicle invasion, and prostate biopsy confirmed acinar adenocarcinoma with a Gleason score of 4+4=8 (ISUP Grade Group 4). Staging investigations revealed clinical stage cT3bN0M0. A chronological summary of the patient’s clinical course and key time points is presented in Table 1. Given the patient’s young age, high-grade disease, and strong paternal family history of prostate cancer, germline testing with an 84-gene panel was performed. Re-evaluation of the original Sanger sequencing chromatogram identified a heterozygous BRCA2 NM_000059.3:c.6500 T>A (p.Leu2167Ter) truncating variant (rs730881543), classified as pathogenic in expert-curated resources. The patient received definitive intensity-modulated radiotherapy (78 Gy) together with long-term androgen-deprivation therapy (goserelin) and abiraterone acetate intensification, based on his high-risk disease features. At 3 months, PSA had declined to 2.1 ng/mL. At 6 months, PSA was 0.35 ng/mL, with marked radiological regression and no evidence of new metastatic disease. This case highlights the value of germline BRCA2 testing in young men with high-risk prostate cancer and a positive family history. It also underscores the importance of verifying variant nomenclature against the original sequencing data. Identification of a pathogenic BRCA2 variant has implications for cascade testing of relatives and may influence future treatment decisions if the disease progresses.