Exome sequencing and case–control analyses identify RCC1 as a candidate breast cancer susceptibility gene

Breast cancer is a genetic disease but the known genes explain a minority of cases. To elucidate the molecular basis of breast cancer in the Tunisian population, we performed exome sequencing on six BRCA1 / BRCA2 mutation‐negative patients with familial breast cancer and identified a novel frameshift mutation in RCC1 , encoding the Regulator of Chromosome Condensation 1. Subsequent genotyping detected the 19‐bp deletion in additional 5 out of 153 (3%) breast cancer patients but in none of 400 female controls ( p  = 0.0015). The deletion was enriched in patients with a positive family history (5%, p  = 0.0009) and co‐segregated with breast cancer in the initial pedigree. The mutant allele was lost in 4/6 breast tumors from mutation carriers which may be consistent with the hypothesis that RCC1 dysfunction provides a selective disadvantage at the stage of tumor progression. In summary, we propose RCC1 as a likely breast cancer susceptibility gene in the Tunisian population.