Utilization of whole exome sequencing to identify hereditary mutations in Palestinian families with hereditary cancers.

Introduction: Hereditary cancers arise from germline pathogenic variants that confer increased lifetime cancer risk. In Palestine, the genetic basis of hereditary cancer predisposition remains limited. The objective of this study is to investigate germline variants associated with hereditary cancer susceptibility in Palestinian families with strong cancer history. Methods: Families with suspected hereditary breast cancer were recruited, and germline DNA extracted from peripheral blood was first analyzed using a BRCA1/2 panel. Whole-exome sequencing (WES) was subsequently performed in BRCA-negative probands to identify additional candidate hereditary variants. A total of 34 individuals from three unrelated families were included in the study, comprising 8 affected and 26 unaffected individuals. Segregation analysis and in silico functional assessment were conducted to evaluate variant pathogenicity. Results: We identified a splice-site variant in RAD50 (c.2524+3A>G) in Family I, a truncating MSH4 variant (c.328C>T; p.R110X) and a missense STAT6 variant (c.1216C>G; p.L406V) in Family II, and a splice-region PRKAR1A variant (c.973+6T>C) in Family III. These variants are segregated with disease in the respective families and are predicted to affect protein function. Conclusion: Our findings highlight the importance of germline genomic analysis in characterizing hereditary cancer predisposition in underrepresented populations and provide preliminary data for future risk assessment and genetic counseling strategies in Palestine.