Carriers of germ-line defects in PALB2 have breast cancer risk estimates overlapping those of BRCA2, and recommendations for risk reduction strategies are similar. Therefore, developing standardized criteria to identify pathogenic variants in PALB2 without incurring overprediction is of paramount clinical relevance. Here, the ENIGMA consortium shows that comprehensive characterization of naturally occurring alternative splicing assists in this task by identifying four locations (the consensus acceptor site of PALB2 exons 2, 5, 7, and 10) in which genetic variants are not necessarily pathogenic. We conclude that the ACMG-AMP criterion of strong evidence of pathogenicity (PVS1) is not warranted for variants at these locations, and they require further exploration to assess their clinical significance.(By Dr. Miguel de la Hoya, https://jmg.bmj.com/content/early/2019/03/19/jmedgenet-2018-105834 )