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MYD88 Mutation Analysis
This test is used to diagnose Waldenstrom macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) and stratify risk of patients with IgM monoclonal gammopathy of undetermined significance (MGUS).
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Test Summary

 

MYD88 Mutation Analysis 

Test code: 91771

 

Clinical use

  • Diagnose Waldenström macroglobulinemia (WM) / lymphoplasmacytic lymphoma (LPL)
  • Inform prognosis and treatment selection for patients with WM/LPL
  • Stratify risk of patients with IgM monoclonal gammopathy of undetermined significance (MGUS)

Clinical background

WM/LPL is characterized by an accumulation of B cells in the bone marrow and overproduction of immunoglobulin M (IgM) protein.1 Approximately 90% of patients with WM/LPL harbor a mutation that leads to increased growth and survival in WM/LPL cells: a leucine to proline mutation at codon 265 (L265P) in the myeloid differentiation primary response 88 gene (MYD88).2,3 Though rare, other mutations in MYD88 have also been identified in WM/LPL patients.4,5

The MYD88 Mutation Analysis assay (test code 91771) can help diagnose WM/LPL in patients with compatible histologic and flow cytometry findings. Because MYD88 mutations do not occur in IgM multiple myeloma and rarely occur in other IgM-related malignancies (eg, marginal zone lymphoma),1,6 the assay helps differentiate WM/LPL from other B-cell lymphoproliferative disorders that have similar clinical features.6

MYD88 mutation status also informs prognosis and treatment selection. Patients with WM/LPL who do not harbor an MYD88 mutation tend to have a more severe disease course and poorer response to treatment with Bruton tyrosine kinase inhibitors (BTKi) than those with an MYD88 mutation.4,7,8 Genetic analysis of MYD88 that can detect L265P and non-L265P mutations is important especially if BTKi treatment is being considered.6

MYD88 mutation status may also assist with risk stratification of IgM MGUS, an asymptomatic, premalignant condition characterized by the presence of monoclonal IgM in the absence of bone marrow disease. Detection rates of MYD88 L265P in patients with IgM MGUS vary widely,1 but some studies suggest that IgM MGUS patients who have the mutation are at increased risk of progression to WM/LPL.9,10

Individuals suitable for testing

  • Individuals with suspected WM/LPL
  • Individuals with IgM MGUS

Method

  • Target-enriched next-generation sequencing by hybridization capture
  • Analytical sensitivity: detects mutant alleles that constitute ≥5% of alleles present in test sample
  • Results reported: presence or absence of mutations in exons 2, 4, and 5 of MYD88, including the L265P mutation

Interpretive information

Presence of an MYD88 mutation is consistent with a diagnosis of WM/LPL in patients with compatible morphologic and immunophenotypic findings. Because MYD88 mutations can occur in some types of large B-cell lymphomas,11 correlation with morphologic findings is essential. Absence of an MYD88 mutation is consistent with the absence of WM/LPL but does not rule out the disease.

In patients with IgM MGUS, presence of the MYD88 L265P mutation suggests an increased risk of progression to WM/LPL.9,10

References

  1. Drandi D, Decruyenaere P, Ferrante M, et al. Nucleic acid biomarkers in Waldenström macroglobulinemia and IgM-MGUS: current insights and clinical relevance. Diagnostics. 2022;12(4):969. doi:10.3390/diagnostics12040969
  2. Treon SP, Xu L, Yang G, et al. MYD88 L265P somatic mutation in Waldenström’s macroglobulinemia. N Engl J Med. 2012;367(9):826-833. doi:10.1056/nejmoa1200710
  3. Xu L, Hunter ZR, Yang G, et al. MYD88 L265P in Waldenström macroglobulinemia, immunoglobulin M monoclonal gammopathy, and other B-cell lymphoproliferative disorders using conventional and quantitative allele-specific polymerase chain reaction. Blood. 2013;121(11):2051-2058. doi:10.1182/blood-2012-09-454355
  4. Treon SP, Xu L, Hunter Z. MYD88 mutations and response to ibrutinib in Waldenström’s macroglobulinemia. N Engl J Med. 2015;373(6):584-586. doi:10.1056/nejmc1506192
  5. Varettoni M, Zibellini S, Defrancesco I, et al. Pattern of somatic mutations in patients with Waldenström macroglobulinemia or IgM monoclonal gammopathy of undetermined significance. Haematologica. 2017;102(12):2077-2085. doi:10.3324/haematol.2017.172718
  6. Dogliotti I, Jiménez C, Varettoni M, et al. Diagnostics in Waldenström’s macroglobulinemia: a consensus statement of the European Consortium for Waldenström’s Macroglobulinemia. Leukemia. 2023;37(2):388-395. doi:10.1038/s41375-022-01762-3
  7. Treon SP, Meid K, Gustine J, et al. Long-term follow-up of ibrutinib monotherapy in symptomatic, previously treated patients with Waldenström macroglobulinemia. J Clin Oncol. 2021;39(6):565-575. doi:10.1200/jco.20.00555
  8. Bustoros M, Sklavenitis-Pistofidis R, Kapoor P, et al. Progression risk stratification of asymptomatic Waldenström macroglobulinemia. J Clin Oncol. 2019;37(16):1403-1411. doi:10.1200/jco.19.00394
  9. Moreno DF, López-Guerra M, Paz S, et al. Prognostic impact of MYD88 and CXCR4 mutations assessed by droplet digital polymerase chain reaction in IgM monoclonal gammopathy of undetermined significance and smouldering Waldenström macroglobulinaemia. Br J Haematol. 2023;200(2):187-196. doi:10.1111/bjh.18502
  10. Varettoni M, Zibellini S, Arcaini L, et al. MYD88 (L265P) mutation is an independent risk factor for progression in patients with IgM monoclonal gammopathy of undetermined significance. Blood. 2013;122(13):2284-2285. doi:10.1182/blood-2013-07-513366
  11. Dubois S, Viailly PJ, Bohers E, et al. Biological and clinical relevance of associated genomic alterations in MYD88 L265P and non-L265P–mutated diffuse large B-cell lymphoma: analysis of 361 cases. Clin Cancer Res. 2017;23(9):2232-2244. doi:10.1158/1078-0432.ccr-16-1922

Content reviewed 09/2025

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91771 - MYD88, Mutation Analysis

Oncogenic mutations in MYD88, in particular the L265P mutation, have been identified as driver mutations in various B-cell lymphomas. The L265P mutation is found in approximately 90% of Waldenstom macroglobulinemia and IgM-expressing lymphoplasmacytic lymphoma (LPL). There is a low incidence of L265P MYD88 mutation in other systemic CD5-negative B-cell lymphoproliferative disorders including atypical chronic lymphocytic leukemia, nodal marginal zone lymphoma (MZL), splenic MZL and mucosa-associated lymphoid tissue (MALT)-type MZL. This next-generation sequencing (NGS) based assay detects clinically significant MYD88 mutations, including the L265P mutation and can be used to help diagnose Waldenstrom macroglobulinemia or IgM-expressing lymphoplasmacytic lymphoma and to help in stratifying or subclassifying patients with IgM monoclonal gammopathy.
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