Identification of rare defective allelic variants in cases of thiopurine S-methyltransferase deficient activity.

To assess rare variants in patients carrying a deficient phenotype not predicted by the four more frequent genotypes and ). Next-generation sequencing of in 39 patients with a discordant genotype. None of the variants identified explained the discordances assuming that they are of uncertain significance according to the Clinical Pharmacogenetics Implementation Consortium classification. Two unknown variants were detected and predicted to result in a splicing defect. We show that  and are defective alleles, and and are associated with a normal activity. Whole-exon sequencing for rare  mutations has a low diagnostic yield. A reassessment of the functional impact of rare variants of uncertain significance is a critical issue.