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BRAF
B-Raf proto-oncogene, serine/threonine kinase
The BRAF gene provides instructions for a protein that plays a crucial role in cell growth, division, and differentiation by helping transmit chemical signals within cells. The BRAF gene is a key component of the RAS/MAPK signalling pathway, which regulates vital cellular processes.
BRAF is located on the long (q) arm of chromosome 7, at band 7q34. Arm ratio per GRCh38 - banding schematic.
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Overview
The BRAF gene, also known as B-Raf proto-oncogene, serine/threonine kinase, is a human gene encoding a protein central to intracellular signal transduction processes. This protein is a key member of the RAS/MAPK signalling pathway, which governs fundamental cellular functions like growth, proliferation, differentiation, movement, and programmed cell death [PMID:22440850].
BRAF is classified as an oncogene, meaning that specific alterations within it can promote the development of cancer. Understanding its function is pivotal for investigating a range of medical conditions, from developmental syndromes to various types of cancer. The gene's role is recognised across several clinical contexts within the NHS Genomic Medicine Service.
What the gene does
The protein produced by the BRAF gene acts as a crucial relay in transmitting chemical signals from a cell's exterior to its nucleus. This signalling process predominantly occurs via the RAS/MAPK pathway, an intricate network of protein interactions. Within this cascade, the BRAF protein functions as a serine/threonine kinase. This enzyme adds phosphate groups to other proteins, thereby modifying their activity and propagating the signal [PMID:22440850]. This complex mechanism is vital for normal embryonic development and maintaining healthy cell populations.
The RAS/MAPK pathway is involved in regulating how cells proliferate and specialise, their movement within tissues, and their programmed self-destruction. Disruptions in this pathway, often caused by changes in genes like BRAF, can lead to uncontrolled cell growth and impaired differentiation, which are characteristic features of cancer. Its role in transmitting these essential signals highlights its importance in both normal physiological processes and disease pathology.
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Chromosome location
The BRAF gene is located on chromosome 7, specifically at position 7q34 on the long arm of the chromosome. This precise genomic address places the gene within a region significant for various cellular functions. Pinpointing the gene's locus on the chromosome provides a fundamental basis for genetic mapping and for identifying chromosomal abnormalities like translocations that could impact BRAF function.
Protein structure
The BRAF protein consists of 766 amino acids and displays a distinct domain organisation essential for its kinase activity. Its N-terminal region, spanning amino acids 1-38, is a Disordered region. This is followed by the RBD (Ras-binding domain) from amino acids 155-227, which facilitates interactions with other proteins in the signalling pathway. A Phorbol-ester/DAG-type (Zinc finger) domain is found between amino acids 234-280, crucial for specific protein-protein interactions. Another Disordered region exists from amino acids 308-454. The core catalytic function resides in the Protein kinase domain, located from amino acids 457-717, which is responsible for phosphorylating target proteins.
Key variants
Genetic variations within the BRAF gene can lead to altered protein function, resulting in a spectrum of potential clinical consequences. These variations may include single nucleotide changes, insertions, or deletions, each affecting the protein's ability to participate effectively in cellular signalling. As BRAF is an oncogene, some variants can disrupt normal cellular regulation. The nature and location of a variant frequently determine its pathogenicity and the specific condition it may be associated with.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1391G>A | p.Gly464Glu | Pathogenic | ★★★☆ | Carcinoma of colon |
c.1406G>A | p.Gly469Glu | Pathogenic | ★★★☆ | Cardiofaciocutaneous syndrome 1 |
c.1455G>C | p.Leu485Phe | Pathogenic | ★★★☆ | Cardiofaciocutaneous syndrome 1 |
c.1455G>T | p.Leu485Phe | Pathogenic | ★★★☆ | RASopathy |
c.1741A>G | p.Asn581Asp | Pathogenic | ★★★☆ | Cardiofaciocutaneous syndrome 1 |
c.1781A>T | p.Asp594Val | Pathogenic | ★★★☆ | RASopathy |
c.1785T>G | p.Phe595Leu | Pathogenic | ★★★☆ | RASopathy |
c.1787G>T | p.Gly596Val | Pathogenic | ★★★☆ | RASopathy |
c.1796C>G | p.Thr599Arg | Pathogenic | ★★★☆ | RASopathy |
c.1796C>T | p.Thr599Ile | Pathogenic | ★★★☆ | RASopathy |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Mutations within the BRAF gene are linked to a range of inherited and somatic conditions affecting various bodily systems. These include developmental disorders such as cardiofaciocutaneous syndrome, which impacts the heart, facial features, skin, and hair. Multiple BRAF mutations have been identified in people with cardiofaciocutaneous syndrome [PMID:16331161]. BRAF variants are also implicated in Erdheim-Chester disease, a rare condition characterised by tissue accumulation of immune cells called histiocytes. The gene is also associated with giant congenital melanocytic nevus [PMID:22057700], Noonan syndrome, and Noonan syndrome with multiple lentigines, both affecting development and presenting with distinctive physical characteristics. Additionally, BRAF mutations are found in cholangiocarcinoma.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic BRAF variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
The BRAF gene is recognised within the UK's NHS Genomic Medicine Service and is included on several Green-rated PanelApp panels, indicating strong evidence for its clinical utility. These panels cover a variety of conditions, including childhood solid tumours cancer susceptibility, DDG2P (Developmental Disorders Genotyping Panel), early onset or syndromic epilepsy, foetal anomalies, and RASopathies. Its presence on these panels highlights its significance in diagnosing and understanding various inherited disorders and cancer predispositions within a UK clinical setting.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
General healthy lifestyle practices, such as maintaining a balanced diet and engaging in regular physical activity, are recommended for overall well-being. However, there is no conclusive evidence that specific lifestyle interventions can prevent or alter the course of conditions associated with BRAF gene variations. Any general recommendations for a healthy lifestyle should always be discussed with a healthcare professional.
Supplement considerations
There is currently no conclusive evidence to suggest that specific dietary supplements can prevent, treat, or mitigate conditions associated with BRAF gene variants. Individuals considering supplements should consult a healthcare provider to discuss potential benefits and risks, particularly given the complex nature of genetic conditions. Nutritional needs are generally best met through a balanced diet, as advised by health professionals.
Frequently asked questions
What is the primary function of the BRAF gene?
The BRAF gene encodes a protein that helps transmit chemical signals within cells as part of the RAS/MAPK pathway. This pathway is crucial for regulating cell growth, division, differentiation, and survival.
How can changes in the BRAF gene affect health?
Changes in the BRAF gene can lead to altered protein function, which may result in uncontrolled cell growth and contribute to cancer, or can cause various developmental syndromes affecting multiple body systems.
Is BRAF associated with cancer?
Yes, BRAF is classified as an oncogene. Mutations in this gene are often found contributing to the development of certain cancers, such as giant congenital melanocytic nevus and cholangiocarcinoma.
What is cardiofaciocutaneous syndrome?
Cardiofaciocutaneous syndrome is a developmental disorder primarily caused by BRAF mutations, affecting the heart, facial features, and the skin and hair [PMID:16331161].
Is the BRAF gene included in UK NHS genetic testing panels?
Yes, the BRAF gene is included on several 'green' rated NHS PanelApp panels. This indicates strong evidence for its clinical relevance in conditions such as cancer susceptibility and various developmental disorders within the UK system.
References
- Salgado CM, Basu D, Nikiforova M. BRAF mutations are also associated with neurocutaneous melanocytosis and large/giant congenital melanocytic nevi. Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society. 2015. PMID: 25490715
- Bosco J, Allende A, Varikatt W. Does the BRAF(V600E) mutation herald a new treatment era for Erdheim-Chester disease? A case-based review of a rare and difficult to diagnose disorder. Internal medicine journal. 2015. PMID: 25735579
- Cives M, Simone V, Rizzo FM. Erdheim-Chester disease: a systematic review. Critical reviews in oncology/hematology. 2015. PMID: 25744785
- Campochiaro C, Tomelleri A, Cavalli G. Erdheim-Chester disease. European journal of internal medicine. 2015. PMID: 25865950
- Harmon CM, Brown N. Langerhans Cell Histiocytosis: A Clinicopathologic Review and Molecular Pathogenetic Update. Archives of pathology & laboratory medicine. 2015. PMID: 26414464
- Rollins BJ. Genomic Alterations in Langerhans Cell Histiocytosis. Hematology/oncology clinics of North America. 2015. PMID: 26461146
- Allen CE, Parsons DW. Biological and clinical significance of somatic mutations in Langerhans cell histiocytosis and related histiocytic neoplastic disorders. Hematology. American Society of Hematology. Education Program. 2015. PMID: 26637772
- Zebary A, Omholt K, van Doorn R. Somatic BRAF and NRAS mutations in familial melanomas with known germline CDKN2A status: a GenoMEL study. The Journal of investigative dermatology. 2014. PMID: 23771122
- Haroche J, Arnaud L, Cohen-Aubart F. Erdheim-Chester disease. Current rheumatology reports. 2014. PMID: 24532298
- Roden AC, Hu X, Kip S. BRAF V600E expression in Langerhans cell histiocytosis: clinical and immunohistochemical study on 25 pulmonary and 54 extrapulmonary cases. The American journal of surgical pathology. 2014. PMID: 24625419
- Satoh T, Smith A, Sarde A. B-RAF mutant alleles associated with Langerhans cell histiocytosis, a granulomatous pediatric disease. PloS one. 2012. PMID: 22506009
- Badalian-Very G, Vergilio JA, Degar BA. Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood. 2010. PMID: 20519626
- Romano AA, Allanson JE, Dahlgren J. Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics. 2010. PMID: 20876176
- Sarkozy A, Carta C, Moretti S. Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum. Human mutation. 2009. PMID: 19206169
- Aoki Y, Niihori T, Narumi Y. The RAS/MAPK syndromes: novel roles of the RAS pathway in human genetic disorders. Human mutation. 2008. PMID: 18470943
- Dhomen N, Marais R. New insight into BRAF mutations in cancer. Current opinion in genetics & development. 2007. PMID: 17208430
- Adam MP, Bick S, Mirzaa GM. Cardiofaciocutaneous Syndrome. 1993. PMID: 20301365
- Adam MP, Bick S, Mirzaa GM. Noonan Syndrome with Multiple Lentigines. 1993. PMID: 20301557