In this scenario, PAX5 germline variants pose the first hit by conferring BCP-ALL susceptibility, whereas the second hit manifests through loss of heterozygosity (LOH) caused by chromosomal 9p aberrations (carrying the PAX5 gene locus), which is somatically detectable in almost 100% of the respective tumors [19]. The gene discussed is PAX5; the disease is acute lymphoblastic leukemia.