Table of Contents

Overview

BRAF mutations, particularly the BRAF V600E hot spot mutation, are primarily associated with hairy cell leukemia and are rare in other B-cell lymphomas. These mutations play a crucial role in the pathogenesis of HCL and have important diagnostic and therapeutic implications. Although they are rare, mutations in BRAF are reproducibly observed in some DLBCLs. Another hot spot, D594A, occurs in DLBCL. The role of these in lymphomagenesis remains poorly understood but functional evidence suggests they may contribute to aneuploidy.1 Although mutations have also been reported in BL, due to minimal support in the original primary data and very few mutations reported in subsequent studies, this gene is very unlikely to be relevant in BL.

Experimental Evidence

Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a reduction or loss of function (LOF).2

Relevance tier by entity

Entity Tier Description
BL 3 Mutations are unlikely to be relevant to BL
DLBCL 1 High-confidence DLBCL gene
MZL 1 High-confidence MZL gene

Warnings

The variants reported in this gene in BL failed QC

Mutation incidence in large patient cohorts (GAMBL reanalysis)

DLBCL

Entity Collection N mutated Incidence 95% CI
DLBCL GAMBL without Reddy 1,089 37 0.0340 [0.0232,0.0447]
DLBCL GAMBL with Reddy 2,088 57 0.0273 [0.0203,0.0343]
DLBCL BC 231 2 0.0087 [0,0.0206]
DLBCL Dana-Farber 303 16 0.0528 [0.0276,0.078]
DLBCL NCI 470 16 0.0340 [0.0176,0.0504]
DLBCL Reddy 999 20 0.0200 [0.0113,0.0287]
DLBCL DLBCL_ICGC 85 3 0.0353 [0,0.0745]

Mutation pattern and selective pressure estimates

Entity Missense dN/dS Nonsense dN/dS Q value
BL 4.6688 0.0000 1.0000
FL 9.6877 0.0000 0.9313
DLBCL 2.7001 1.1494 0.0364

BRAF Hotspots

V600E The V600E mutation, which is common in other cancers including hairy cell leukemia, is observed in some DLBCL patients. This mutation mimics phosphorylation and leads to constitutive activation of the BRAF kinase. As a result, the V600E mutant continuously activates the MAPK/ERK signaling pathway, promoting cell proliferation and survival even in the absence of growth signals.

D594 Mutations of this residue have a distinct function than V600E. In particular, D594A results in a kinase-inactive form of BRAF. Unlike the V600E mutation, D594A does not directly activate the MAPK/ERK pathway. Instead, it induces aneuploidy and contributes to cancer progression through the activation of the related gene product CRAF. This activation leads to the downstream activation of the MEK/ERK pathway via CRAF, rather than BRAF.

Chromosome Coordinate (hg19) ref>alt HGVSp
chr7 140453155 C>T D594N
chr7 140453154 T>G D594A
chr7 140453154 T>C D594G
chr7 140453145 A>T L597Q
chr7 140453136 A>T V600E
chr7 140453132 T>G K601N
Structure with HotMAPS hotspots

Visualizations

Protein

View coding variants in ProteinPaint hg19 or hg38

Genome

View all variants in GenomePaint hg19 or hg38

Expression

Representative Mutations

BL3

Rating ★ ☆ ☆ ☆ ☆

All Mutations

BL

1102 673

History

%%{init: { 'logLevel': 'debug', 'theme': 'dark' } }%% timeline title Publication timing 2011-06-16 : Tiacci : DLBCL 2012-12-01 : Love : BL 2018-05-01 : Chapuy : DLBCL 2021-05-05 : Hubschmann : DLBCL

References

1.
Tiacci E, Trifonov V, Schiavoni G, Holmes A, Kern W, Martelli MP, Pucciarini A, Bigerna B, Pacini R, Wells VA, Sportoletti P, Pettirossi V, Mannucci R, Elliott O, Liso A, Ambrosetti A, Pulsoni A, Forconi F, Trentin L, Semenzato G, Inghirami G, Capponi M, Di Raimondo F, Patti C, Arcaini L, Musto P, Pileri S, Haferlach C, Schnittger S, Pizzolo G, Foà R, Farinelli L, Haferlach T, Pasqualucci L, Rabadan R, Falini B. BRAF mutations in hairy-cell leukemia. N Engl J Med. 2011 Jun 16;364(24):2305–2315. PMCID: PMC3689585
2.
Wan PTC, Garnett MJ, Roe SM, Lee S, Niculescu-Duvaz D, Good VM, Jones CM, Marshall CJ, Springer CJ, Barford D, Marais R, Cancer Genome Project. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell. 2004 Mar 19;116(6):855–867.
3.
Love C, Sun Z, Jima D, Li G, Zhang J, Miles R, Richards KL, Dunphy CH, Choi WWL, Srivastava G, Lugar PL, Rizzieri DA, Lagoo AS, Bernal-Mizrachi L, Mann KP, Flowers CR, Naresh KN, Evens AM, Chadburn A, Gordon LI, Czader MB, Gill JI, Hsi ED, Greenough A, Moffitt AB, McKinney M, Banerjee A, Grubor V, Levy S, Dunson DB, Dave SS. The genetic landscape of mutations in Burkitt lymphoma. Nat Genet. 2012 Dec;44(12):1321–1325. PMCID: PMC3674561

Citing

If you use the information or data from this site, please cite

Krysta Coyle, Kostiantyn Dreval, Daniel Hodson and Ryan D. Morin. Audit of B-cell cancer genes. Blood Adv (2025) 9 (8): 2019–2031.

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