Preliminary results of targeted sequencing of and in a cohort of breast cancer families: New insight into pathogenic variants in patients and at‑risk relatives.

Breast cancer (BC) is the most commonly diagnosed cancer worldwide and a major health concern in Egypt. There is a known association between pathogenic variants identified in breast cancer susceptibility gene ()1 and 2 and the risk of developing BC. However, the number of studies investigating mutations in and in Egypt remains limited. Thus, the aim of the present study was to investigate the frequency of and variants in patients with BC and their relatives. For this purpose, 11 families (11 patients and 16 relatives) were included in the present study. and variants were investigated using the Ion S5 next‑generation sequencer. It was found that pathogenic variants were more frequent in patients with familial BC (FBC) than in those with sporadic BC, with 71% of variants in , including the first reported identification of c.9089del, c.5583_5584dup, c.8243G>A and c.7976G>A pathogenic variants in Egyptian patients with BC. Pathogenic variants in relatives were confined to FBC c.1278delA, c.1960_1961del, and c.1224delT, with a higher incidence of variants of uncertain significance (VUS), such as intron 2 c.68‑16delT. Of note, two cold spot benign variants, c.3113A>G and c.4837A>G, were repeatedly found (67%) in patients and relatives. In conclusion, to the best of our knowledge, novel pathogenic variants and VUS in Egyptian patients with BC and their high‑risk relatives were identified for the first time in the present study. These findings should be integrated with other genomic data concerning Egyptian families and carefully interpreted during genetic counseling.