Spectrum of BRCA1/2 pathogenic variants in Southern and Western Asia-a systematic review

BRCA1/2 germline variants account for 5-10 % of breast cancers (BC) or up to 25 % of hereditary breast cancers, yet data on their prevalence in South Asia and the Middle East remains limited. This study investigates germline BRCA1/2 pathogenic variants (PVs) in eight South Asian Association for Regional Cooperation (SAARC) and six Gulf Cooperation Council (GCC) countries, providing insights into the regional mutation landscape. Systematic literature search identified 46 studies and all reported BRCA1/2 variants from each study were re-interpreted using ClinVar and BRCA Exchange to determine pathogenicity. In both cohorts, the median age of BC diagnosis was < 40 years. A total of 159 BRCA1 and 100 BRCA2 PVs were reported in 772 index South Asian and Middle Eastern BC cases. Only 10 BRCA1/2 PVs (6 %) overlapped between the two cohorts, while 141 BRCA1 and 98 BRCA2 PVs were exclusive to either SAARC or GCC cohorts. BRCA1 c.68_69del was the most recurrent PV (n = 111). Overall, BRCA1 PVs were prevalent in early-onset (83 %), triple-negative (95 %), and familial BC disease (80 %). In SAARC cohort, BRCA1 exon 11 and BRCA2 exon 15 were most frequently mutated exons. In GCC cohort, exon 18 of BRCA1 and BRCA2 exon 13 were the hotspot regions. Our findings highlight the necessity for population-specific genetic testing and indicate a clear regional genetic propensity in BRCA gene. To our knowledge, this dataset represents the largest collection of BRCA1/2 PVs from SAARC and GCC nations, and may act as a resource for future studies.