Pathogenic germline variants in BRCA1 and BRCA2 genes confer increased breast/ovarian cancer (BC/OC) risks.

The identification of deleterious BRCA1/2 genetic variants in BC/OC families guides the enrollment of carriers in medical surveillance and cancer prevention programs and informs treatment decisions by more precisely targeted cancer therapies.

BRCA1/2 genetic analysis commonly includes only coding regions. However, no deleterious variant is identified in a significant fraction of families. We have studied the intronic regions of these genes to identify pathogenic variants that would be undetected during conventional testing. We describe the first BRCA1 deep intronic variant linked to pathogenicity by disrupting splicing and promoting the inclusion of a pseudoexon. Our results support the application of whole-gene sequencing in the clinical setting in order to identify variants that could explain the missing heritability. (By Gemma Montalban, https://jmg.bmj.com/content/early/2018/11/24/jmedgenet-2018-105606 )