Familial BCP-ALL with heterozygous germline PAX5 R38H mutation. (A) The germline R38H variant was shown to be inherited from 1 parent (I.2) who is so far an asymptomatic carrier with no history of cancer at age 68 years. The proband (II.2, indicated by an arrow) developed BCP-ALL at age 17 years. He relapsed 2 years after his initial diagnosis and was allografted with his brother (II.3) as a donor 14 years before II.3 also developed BCP-ALL. II.2 relapsed at age 40 years and died soon thereafter as a result of an intracranial hemorrhage. His sister (II.1) developed BCP-ALL at age 11 years for which she received chemotherapy without HSCT. She is still in CR more than 30 years after her initial diagnosis. The proband’s younger brother (II.3) also developed also BCP-ALL at age 25 years and died of infectious complications after HSCT from an unrelated donor. (+) Indicates the presence of the R38H germline mutation. (B) Sanger sequencing of PAX5 mutation in samples of I.1, I.2, II.1, II.2, and II.3; the location of the mutation is indicated by an arrow demonstrating a germline origin. The nucleotide and protein sequences are indicated at the bottom of the panel. (C) Representative image of May-Grünwald-Giemsa–stained bone marrow smear at BCP-ALL diagnosis in individual II.1. (D) Somatic PAX5 mutations in leukemic samples from individuals II.1 (top) and II.3 (bottom). Positions of mutations are indicated by red arrows. (E-F) Leukemic architecture at BCP-ALL diagnosis in individual II.3 (donor) (E) and at donor-related BCP-ALL in individual II.2 (recipient) (F). Variant allele frequency (VAF) for each mutation is indicated.