Whole exome sequencing reveals rare DNA repair gene variants in BRCA1/2-negative Arab early-onset breast cancer patients.

Early-onset Breast Cancer (EOBC), defined as breast cancer diagnosed at or before the age of 40 years, represents a small but clinically aggressive subset of breast cancer cases. While pathogenic variants in BRCA1/2 might explain some of this risk, many EOBC cases remain unexplained. This study aimed to investigate rare germline variants in DNA repair genes that may contribute to EOBC among BRCA1/2-negative patients of Arab ancestry. We performed germline whole exome sequencing (WES) on a cohort of 79 BRCA1/2 negative EOBC patients (median age 28 years, range 13-39). Rare variants (minor allele frequency < 1%) in 217 curated DNA repair genes were filtered and prioritized using CADD and REVEL scores. Protein structure modeling was conducted for selected novel variants to evaluate their potential impact on protein function. Seventy rare deleterious variants were identified across the analyzed DNA repair genes. Among these, five novel variants were identified in DNA2, CLK2, EME2, SWI5 and RAD51B, the latter harboring a frameshift variant indicative of loss of function. Structured modeling revealed that three novel missense variants - DNA2, CLK2 and EME2 - were predicted to introduce localized structural changes that may affect protein function. Several patients carried multiple deleterious variants, suggesting a possible polygenic contribution to EOBC predisposition. These findings expand the spectrum of rare DNA repair gene variants observed in BRCA1/2-negative early-onset breast cancer and provide candidate variants for further investigation, rather than establishing definitive causal associations.