However, phenotypic severity or penetrance can be influenced by the genotype at another locus, which is referred to as a modifier gene.35 Indeed, in hereditary breast cancer, polygenic risk scores (PRSs) for ovarian cancer are associated with penetrance of ovarian cancer in BRCA1/BRCA2 variant carriers.36 GPSEA could be easily extended to evaluate the effects of PRSs or variants in modifier genes, but the main challenge will be in the collection of comprehensive clinical and genomic data. The gene discussed is BRCA2; the disease is breast cancer.