Comprehensive genomic analysis of non-BRCA familial breast cancer in an Arab population

The Middle East and North African (MENA) region broadly mirrors global cancer trends, with breast cancer remaining the most common cancer among women. However, regional differences in germline BRCA1/2 mutation prevalence suggest the presence of additional genetic risk factors across MENA subgroups. We analyzed whole genome sequencing data from 180 non-BRCA familial breast cancer patients from Jordan and approximately 6000 healthy Arab controls to identify rare germline variants in cancer genes, and to evaluate the performance of existing breast cancer polygenic risk scores (PRS). Three loss-of-function variants in the high-penetrance breast cancer genes TP53 and PALB2 were exclusively observed in patients, including one TP53 variant of uncertain significance. Multiple pathogenic or likely pathogenic variants were detected in moderate-penetrance breast cancer genes, including ATM and BARD1, with ATM showing significant enrichment in gene burden analysis (OR = 14.84). Two rare loss-of-function variants in PASK and CHEK1, lacking clinical significance, were observed in multiple patients but not in controls. PRS assessment identified four PRSs with good discriminatory power (AUC > 0.690), with PGS003738 showing the highest performance (AUC = 0.702, top decile OR = 3.57). These findings highlight the need for population-specific genetic studies to improve breast cancer risk stratification in Arab populations.