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Mutations inCXCR4have been identified in ˜29% of patients with Waldenstrom macroglobulinemia having theMYD88L265P mutation.CXCR4mutations interfere with treatment response to ibrutinib. We designed and validated Sanger sequencing and pyrosequencing assays to detect mutations inCXCR4in a Clinical Laboratory Improvement Amendments-approved clinical laboratory. We identifiedCXCR4mutations in 8 of 33 low grade B-cell lymphomas examined.Waldenstrom macroglobulinemia (WM) is a B-cell lymphoma characterized by the accumulation of lymphocytes and plasmacytic cells in the bone marrow and by excess production of immunoglobulin M in serum. WM has been closely linked with the MYD88L265P mutation. Whole genome sequencing has identified somatic mutations in the CXCR4 gene in ˜29% of WM cases with MYD88L265P. CXCR4 mutations may interfere with treatment response to ibrutinib. The goal of this study was to design and validate a clinical assay to detect CXCR4 mutations.Thirty-three low-grade B-cell lymphomas with plasmacytic differentiation (23 MYD88L265P and 10 MYD88WT) involving various samples types (fresh and formalin-fixed tissues) formed the study group. We designed and validated Sanger sequencing and pyrosequencing assays to detect mutations in CXCR4 in a Clinical Laboratory Improvement Amendments-approved clinical laboratory.We identified 8 cases with CXCR4 mutations, including 5 single nucleotide substitutions (3 resulting in p.S338* and 1 in p.R334*), and 3 insertion/deletions. Seven of 8 CXCR4 mutated cases were also MYD88L265P mutant. Among the single nucleotide substitutions, we identified a novel missense variant (p.L326P) and a previously reported variant (G335S) of uncertain clinical significance.We successfully validated a set of clinical assays to detect mutations in CXCR4 mutations in a clinical laboratory.