NM_002468.5(MYD88):c.755T>C (p.Leu252Pro) AND Macroglobulinemia, Waldenstrom, somatic

Clinical significance:Pathogenic (Last evaluated: Dec 6, 2012)

Review status:(0/4) 0 stars out of maximum of 4 stars

no assertion criteria provided

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000030709.6

Allele description [Variation Report for NM_002468.5(MYD88):c.755T>C (p.Leu252Pro)]

NM_002468.5(MYD88):c.755T>C (p.Leu252Pro)

Gene:
MYD88:MYD88 innate immune signal transduction adaptor [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
3p22.2
Genomic location:
Preferred name:
NM_002468.5(MYD88):c.755T>C (p.Leu252Pro)
Other names:
L265P; *160R; *192R; *246R; *147R; *201R
HGVS:
  • NC_000003.12:g.38141150T>C
  • NG_016964.1:g.7673T>C
  • NG_023225.1:g.1093A>G
  • NM_001172566.2:c.439T>C
  • NM_001172567.2:c.779T>C
  • NM_001172568.2:c.620T>C
  • NM_001172569.3:c.574T>C
  • NM_001365876.1:c.736T>C
  • NM_001365877.1:c.601T>C
  • NM_001374787.1:c.712T>C
  • NM_001374788.1:c.287T>C
  • NM_002468.5:c.755T>CMANE SELECT
  • NP_001166037.2:p.Ter147Arg
  • NP_001166038.2:p.Leu260Pro
  • NP_001166039.2:p.Leu207Pro
  • NP_001166040.2:p.Ter192Arg
  • NP_001352805.1:p.Ter246Arg
  • NP_001352806.1:p.Ter201Arg
  • NP_001361716.1:p.Ter238Arg
  • NP_001361717.1:p.Leu96Pro
  • NP_002459.3:p.Leu252Pro
  • LRG_157:g.7673T>C
  • NC_000003.11:g.38182641T>C
  • NM_002468.4:c.794T>C
  • NR_164663.1:n.438T>C
Note:
Note that rs38182641, from OMIM 602170.0004, is incorrect.
Protein change:
L207P; LEU265PRO
Links:
OMIM: 602170.0004; dbSNP: rs387907272
NCBI 1000 Genomes Browser:
rs387907272
Molecular consequence:
  • NM_001172567.2:c.779T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001172568.2:c.620T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001374788.1:c.287T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002468.5:c.755T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NR_164663.1:n.438T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NM_001172566.2:c.439T>C - stop lost - [Sequence Ontology: SO:0001578]
  • NM_001172569.3:c.574T>C - stop lost - [Sequence Ontology: SO:0001578]
  • NM_001365876.1:c.736T>C - stop lost - [Sequence Ontology: SO:0001578]
  • NM_001365877.1:c.601T>C - stop lost - [Sequence Ontology: SO:0001578]
  • NM_001374787.1:c.712T>C - stop lost - [Sequence Ontology: SO:0001578]

Condition(s)

Name:
Macroglobulinemia, Waldenstrom, somatic
Identifiers:
MedGen: C3549870

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000053370OMIMno assertion criteria providedPathogenic
(Dec 6, 2012)
somaticliterature only

PubMed (3)
[See all records that cite these PMIDs]

Treon, S. P., Xu, L., Hunter, Z. R. Reply to Landgren and Staudt. (Letter) New Eng. J. Med. 367: 2256-2257, 2012.

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedsomaticnot providednot providednot providednot providednot providednot providedliterature only

Citations

PubMed

Oncogenically active MYD88 mutations in human lymphoma.

Ngo VN, Young RM, Schmitz R, Jhavar S, Xiao W, Lim KH, Kohlhammer H, Xu W, Yang Y, Zhao H, Shaffer AL, Romesser P, Wright G, Powell J, Rosenwald A, Muller-Hermelink HK, Ott G, Gascoyne RD, Connors JM, Rimsza LM, Campo E, Jaffe ES, et al.

Nature. 2011 Feb 3;470(7332):115-9. doi: 10.1038/nature09671. Epub 2010 Dec 22.

PubMed [citation]
PMID:
21179087
PMCID:
PMC5024568

MYD88 L265P somatic mutation in Waldenström's macroglobulinemia.

Treon SP, Xu L, Yang G, Zhou Y, Liu X, Cao Y, Sheehy P, Manning RJ, Patterson CJ, Tripsas C, Arcaini L, Pinkus GS, Rodig SJ, Sohani AR, Harris NL, Laramie JM, Skifter DA, Lincoln SE, Hunter ZR.

N Engl J Med. 2012 Aug 30;367(9):826-33. doi: 10.1056/NEJMoa1200710.

PubMed [citation]
PMID:
22931316
See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000053370.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (3)

Description

Ngo et al. (2011) described the dependence of activated B cell-like (ABC) diffuse large B-cell lymphoma (DLBCLs) on MYD88 and the discovery of highly recurrent oncogenic mutations affecting MYD88 in ABC DLBCL tumors. RNA interference screening revealed that MYD88 and the associated kinases IRAK1 (300283) and IRAK4 (606883) are essential for ABC DLBCL survival. High-throughput RNA resequencing uncovered MYD88 mutations in ABC DLBCL lines. Notably, 29% of ABC DLBCL tumors harbored the same amino acid substitution, L265P, in the MYD88 Toll/IL1 receptor (TIR) domain at an evolutionarily invariant residue in its hydrophobic core. This mutation was rare or absent in other DLBCL subtypes and Burkitt lymphoma (113970), but was observed in 9% of mucosa-associated lymphoid tissue lymphomas. At a lower frequency, additional mutations were observed in the MYD88 TIR domain, occurring in both the ABC and germinal center B cell-like (GCB) DLBCL subtypes. Survival of ABC DLBCL cells bearing the L265P mutation was sustained by the mutant but not the wildtype MYD88 isoform, demonstrating that L265P is a gain-of-function driver mutation. The L265P mutant promoted cell survival by spontaneously assembling a protein complex containing IRAK1 and IRAK4, leading to IRAK4 kinase activity, IRAK1 phosphorylation, NF-kappa-B (see 164011) signaling, JAK kinase (see 147795) activation of STAT3 (102582), and secretion of IL6 (147620), IL10 (124092), and interferon-beta (147640). Hence, Ngo et al. (2011) concluded that the MYD88 signaling pathway is integral to the pathogenesis of ABC DLBCL, supporting the development of inhibitors of IRAK4 kinase and other components of this pathway for the treatment of tumors bearing oncogenic MYD88 mutations.

Treon et al. (2012) performed whole-genome sequencing of bone marrow lymphoplasmacytic lymphoma (LPL) cells in 30 patients with Waldenstrom macroglobulinemia (153600), with paired normal-tissue and tumor-tissue sequencing in 10 patients. Sanger sequencing was used to validate the findings from an expanded cohort of patients with LPL, those with other B-cell disorders that have some of the same features as LPL, and healthy donors. Among the patients with Waldenstrom macroglobulinemia, Treon et al. (2012) identified a somatic mutation, L265P, in samples from all 10 patients with paired tissue samples and in 17 of 20 samples from patients with unpaired samples. This T-to-C transition at genomic position 38182641 predicted an amino acid change that triggers IRAK-mediated NF-kappa-B signaling. Sanger sequencing identified MYD88 L265P in tumor samples from 49 of 54 patients with Waldenstrom macroglobulinemia and in 3 of 3 patients with non-IgM-secreting lymphoplasmacytic lymphoma (LPL) (91% of all patients with LPL). MYD88 L265P was absent in paired normal-tissue samples from patients with Waldenstrom macroglobulinemia or non-IgM LPL and in B cells from healthy donors and was absent or rarely expressed in samples from patients with multiple myeloma, marginal-zone lymphoma, or IgM monoclonal gammopathy of unknown significance. Inhibition of MYD88 signaling reduced I-kappa-B-alpha (164008) and NF-kappa-B p65 (164014) phosphorylation, as well as NF-kappa-B nuclear staining, in Waldenstrom macroglobulinemia cells expressing MYD88 L265P. Similar results were obtained when cells expressing MYD88 L265P were incubated with an IRAK1/4 kinase inhibitor. Somatic variants in ARID1A (603024) in 5 of 30 patients (17%), leading to a premature stop or frameshift, were also identified and were associated with an increased disease burden. In addition, 2 of 3 patients with Waldenstrom macroglobulinemia who had wildtype MYD88 had somatic variants in MLL2 (602113). Treon et al. (2012) concluded that MYD88 L265P is a commonly recurring mutation in patients with Waldenstrom macroglobulinemia that can be useful in differentiating Waldenstrom macroglobulinemia and non-IgM LPL from B-cell disorders that have phenotypic overlap.

Landgren and Staudt (2012) used Sanger sequencing to assess the status of MYD88 L265P expression in patients with IgM monoclonal gammopathy of undetermined significance (MGUS) and found expression of this variant in 5 of 9 patients. All of these patients had both clonal plasma cells and clonal lymphocytes in bone marrow (lymphoplasmacytic precursor neoplasm), suggesting to Landgren and Staudt (2012) that this mutation is a precursor to Waldenstrom macroglobulinemia rather than transformation from IgM MGUS to Waldenstrom macroglobulinemia. Treon et al. (2012) commented that, to overcome the limitations of Sanger sequencing, they developed an allele-specific polymerase chain reaction (AS-PCR) assay to detect the MYD88 L265P mutation with a threshold detection limit of 0.1% (approximately 100-fold better than that of Sanger sequencing). They found that 88 of 96 patients with Waldenstrom macroglobulinemia (92%) and 5 of 11 patients with IgM MGUS (45%), as defined by consensus criteria, were positive for MYD88 L265P expression by either conventional or quantitative AS-PCR assays. Treon et al. (2012) concluded that IgM MGUS is heterogeneous and that MYD88 L265P is probably a driver mutation toward Waldenstrom macroglobulinemia.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1somaticnot providednot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 8, 2021

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