Abstract
Fanconi anemia (FA) is a DNA repair deficiency disorder associated with genomic and chromosomal instability and a high cancer risk. In a small percentage of cases, FA is caused by biallelic pathogenic variants (PVs) in the BRCA2/FANCD1 gene, defining the FA-D1 subtype. Experimental and epidemiologic data indicate that the complete absence of BRCA2 is incompatible with viability. Therefore, cells from individuals affected with FA caused by biallelic BRCA2 PVs must have a residual BRCA2 function. This activity may be maintained through hypomorphic missense mutations, translation termination-reinitiation associated with a translational stop mutation, or other non-canonical or uncommon translation initiation and elongation events. In some cases, however, residual BRCA2 function is provided by alternatively or aberrantly spliced BRCA2 transcripts. Here, we review and debate aspects of the contribution of splicing in the 5' segment to BRCA2 functions in the context of PVs affecting this largely intrinsically disordered protein region, with a focus on recent findings in individuals with FA-D1. In this Perspective, we also discuss some of the broader biological implications and open questions that arise from considering 5'-terminal BRCA2 splicing in light of old and new findings from FA-D1 patients and beyond.