Detection and characterization of germ line NBN variants in childhood B-cell ALL (B-ALL). Targeted sequencing of NBN was performed in 4325 patients with B-ALL enrolled in the Children’s Oncology Group and St. Jude Children’s Research Hospital trials (left). Rare (allele frequency, <0.001) and predicted deleterious (Combined Annotation Dependent Depletion [CADD] score, >20) variants were identified in 1.2% of patients, and in 0.4% of controls (n = 118 479) using summary counts from whole-exome sequencing (WES) in the Genome Aggregation Database. Ancestry stratified analysis of enrichment of NBN variants in B-ALL was conducted using CoCoRV, with patients and controls split into 5 ancestry groups, defined as non-Finnish European, African American, admixed American (Hispanic/Latino), South Asian, and East Asian individuals (as represented by the different colors). Of the 25 rare and predicted deleterious NBN variants identified in patients, 14 were experimentally shown to be nonfunctional or partially functional based on protein stability and drug sensitivity assays. OR, odds ratio. Figure created with BioRender.com.