BRAF
protein-codingB-Raf proto-oncogene, serine/threonine kinase, the group of RAF family|Mitogen-activated protein kinase kinase kinases
Gene summary
This gene encodes a protein belonging to the RAF family of serine/threonine protein kinases. This protein plays a role in regulating the MAP kinase/ERK signaling pathway, which affects cell division, differentiation, and secretion. Mutations in this gene, most commonly the V600E mutation, are the most frequently identified cancer-causing mutations in melanoma, and have been identified in various other cancers as well, including non-Hodgkin lymphoma, colorectal cancer, thyroid carcinoma, non-small cell lung carcinoma, hairy cell leukemia and adenocarcinoma of lung. Mutations in this gene are also associated with cardiofaciocutaneous, Noonan, and Costello syndromes, which exhibit overlapping phenotypes. A pseudogene of this gene has been identified on the X chromosome. [provided by RefSeq, Aug 2017]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~205.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0013379
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0013380
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0007265
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0015280
Submitter: ClinGen
There is a definitive association between alteration of the BRAF gene and cardiofaciocutaneous (CFC) syndrome. The maximum amount of scorable genetic evidence has been published showing de novo as well as non-de novo variants occur in BRAF in patients with CFC syndrome (Gripp et al., 2007; Louati et al., 2014; Makita et al., 2007; Mucciolo, Dello Russo, D'Emidio, Mesoraca, & Giorlandino, 2016; Narumi et al., 2007; Niihori et al., 2006; Rodriguez-Viciana, Tetsu, et al., 2006). The BRAF gene is located in the Ras/MAPK pathway which is associated with the Noonan phenotype and variants found in CFC patients in this gene disrupt the RAS pathway function as demonstrated by both mouse and zebrafish models (Anastasaki, Estep, Marais, Rauen, & Patton, 2009; Aoki et al., 2016; Moriya et al., 2015; Rauen, 2013). Of note, BRAF has also been classified as moderate in association with Noonan syndrome (NS), limited in association with NS with multiple lentigines, and disputed in association with Costello syndrome. The ClinGen RASopathy Expert Panel found no evidence associating BRAF with NS with loose anagen hair. This curation was approved by the ClinGen RASopathy Gene Curation Expert Panel on 7/24/18 (SOP Version 5).
Inheritance Pattern: AD
Disease ID:MONDO:0013379
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0013380
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0009026
Submitter: ClinGen
Only one study to date has identified variants in BRAF in patients diagnosed with suspected Costello syndrome. However, due to lack of further evidence for impact of these variants as well as variable expressivity, age of ascertainment, and outdated clinical assessments of affected individuals, these cases were not scored and, therefore, this gene-disease association is classified as Disputed. Furthermore, the HRAS gene is believed to be the only gene definitively associated with Costello syndrome (Aoki et al., 2005; Estep, Tidyman, Teitell, Cotter, & Rauen, 2006; Gripp et al., 2006; Kerr et al., 2006; Zampino et al., 2007). Of note, BRAF has also been classified as definitive in association with cardiofaciocutaneous syndrome, moderate in association with Noonan syndrome (NS), and limited in association with NS with multiple lentigines. The ClinGen RASopathy Expert Panel found no evidence associating BRAF with NS with loose anagen hair. This curation was approved by the ClinGen RASopathy Gene Curation Expert Panel on 7/24/18 (SOP Version 5).
Inheritance Pattern: AD
Disease ID:MONDO:0013379
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0013379
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0007893
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0015280
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0013380
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0007265
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0013380
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0018997
Submitter: ClinGen
There was sufficient genetic evidence in the literature for the association between BRAF and Noonan syndrome (NS) to be classified as Moderate. However, variable expressivity, age of ascertainment, and outdated clinical assessments of affected individuals may complicate the clinical diagnosis of NS versus cardiofaciocutaneous syndrome (CFC). Additional genotype-phenotype correlations are necessary to solidify the association of BRAF with Noonan syndrome (Lee et al., 2011; Nystrom et al., 2008; Razzaque et al., 2007; Sarkozy et al., 2009; van Trier et al., 2016). The BRAF gene is also located in the Ras/MAPK pathway which is associated with the NS phenotype (Aoki, Niihori, Inoue, & Matsubara, 2016; Rauen, 2013). Of note, BRAF has also been classified as definitive in association with CFC, limited in association with NS with multiple lentigines, and disputed in association with Costello syndrome. The ClinGen RASopathy Expert Panel found no evidence associating BRAF with NS with loose anagen hair. This curation was approved by the ClinGen RASopathy Gene Curation Expert Panel on 7/24/18 (SOP Version 5).
Inheritance Pattern: AD
Disease ID:MONDO:0013379
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0007265
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0013380
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0016684
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0007893
Submitter: ClinGen
There was only sufficient evidence in the literature for the association between BRAF and Noonan syndrome with multiple lentigines (NSML) to be classified as Limited. Variable expressivity, age of ascertainment, and outdated clinical assessments of affected individuals may complicate the clinical diagnosis of NSML versus other BRAF-RASopathies. Additional genotype-phenotype correlations are necessary to solidify the association of BRAF with NSML. Of note, variants identified in patients with cardiofaciocutaneous syndrome (CFC) diagnoses have also been identified in patients with NS, thus complicating the possibility of a genotype-phenotype correlation (Carcavilla et al., 2013; Ezquieta et al., 2012; Koudova, Seemanova, & Zenker, 2009; Sarkozy et al., 2009). The BRAF gene is also located in the Ras/MAPK pathway which is directly associated with the NSML phenotype (Aoki et al., 2016; Rauen, 2013). Additionally, BRAF has been classified as definitive in association with CFC syndrome, moderate in association with NS, and disputed in association with Costello syndrome. The ClinGen RASopathy Expert Panel found no evidence associating BRAF with NS with loose anagen hair. This curation was approved by the ClinGen RASopathy Gene Curation Expert Panel on 7/24/18 (SOP Version 5).
Inheritance Pattern: AD
Disease ID:MONDO:0044792
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0007265
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0007265
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Craniofacial; Dermatologic; Genitourinary; Hematologic; Musculoskeletal; Neurologic; Oncologic; Ophthalmologic;
Intervention: Cardiovascular; Hematologic; Oncologic
Rationale: Surveillance and treatment related tomanifestations such as cardiac anomalies (which include pulmonic stenosis, hypertrophic cardiomyopathy, and arrhythmias) can be beneficial; The disorders can include bleeding diathesis, and recognition and preventive measures (eg, in surgical situations) can be beneficial; Individuals with malignancies (eg, ALL) have been reported, and awareness of increased risk may be beneficial
Comments: The conditions may be frequently clinically recognized due to characteristic facial features as well as other manifestations
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to BRAF variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_004333.6. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 16 | 306 | 12 | 334 | ||
| missense | 54 | 88 | 504 | 25 | 4 | 675 |
| nonsense | 1 | 13 | 14 | |||
| start loss | 1 | 1 | ||||
| frameshift | 35 | 35 | ||||
| splice donor/acceptor (+/-2bp) | 1 | 12 | 13 | |||
| Total | 56 | 88 | 581 | 331 | 16 | 1072 |
Highest pathogenic variant AF is 0.000004794435
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_004324.2 | 18 | MANE Select | |
| Ensembl | ENSP00000493543.1 | 18 | MANE Select | |
| RefSeq | NP_001341538.1 | 19 | Standard | |
| RefSeq | NP_001361173.1 | 19 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Non-small cell lung cancer - Homo sapiens (human)
- Chronic myeloid leukemia - Homo sapiens (human)
- Gastric cancer - Homo sapiens (human)
- Focal adhesion - Homo sapiens (human)
- mTOR signaling pathway - Homo sapiens (human)
Biological Process
- MAPK cascade
- activation of MAPKK activity
- myeloid progenitor cell differentiation
- protein phosphorylation
- visual learning
Molecular Function
- protein kinase activity
- protein serine/threonine kinase activity
- MAP kinase kinase kinase activity
- calcium ion binding
- protein binding
Cellular Component
- nucleus
- mitochondrion
- cytosol
- plasma membrane
- neuron projection
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000288602
- Coding exons
- 18
- Length
- 205438
- Individuals with no LoFs
- 125742
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 6
- Defined
- 125748
- p
- 0.0000239
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 3.72 | 203 | 417 | 0.487 | 0.0000215 | 4958 |
| Missense (PolyPhen) | 38 | 127.38 | 0.29833 | 1588 | ||
| Synonymous | -0.223 | 157 | 153 | 1.02 | 0.00000807 | 1528 |
| Loss of Function | 5.91 | 5 | 50.2 | 0.0996 | 0.00000324 | 511 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000035 | 0.000035 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Protein kinase involved in the transduction of mitogenic signals from the cell membrane to the nucleus. May play a role in the postsynaptic responses of hippocampal neuron. Phosphorylates MAP2K1, and thereby contributes to the MAP kinase signal transduction pathway. {ECO:0000269|PubMed:21441910}.;
- Disease
- DISEASE: Note=Defects in BRAF are found in a wide range of cancers. {ECO:0000269|PubMed:18974108}.; DISEASE: Colorectal cancer (CRC) [MIM:114500]: A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. {ECO:0000269|PubMed:12198537, ECO:0000269|PubMed:21917714, ECO:0000269|PubMed:23263490, ECO:0000269|PubMed:24455489}. Note=The disease may be caused by mutations affecting the gene represented in this entry.; DISEASE: Lung cancer (LNCR) [MIM:211980]: A common malignancy affecting tissues of the lung. The most common form of lung cancer is non-small cell lung cancer (NSCLC) that can be divided into 3 major histologic subtypes: squamous cell carcinoma, adenocarcinoma, and large cell lung cancer. NSCLC is often diagnosed at an advanced stage and has a poor prognosis. {ECO:0000269|PubMed:12460919}. Note=The gene represented in this entry is involved in disease pathogenesis.; DISEASE: Familial non-Hodgkin lymphoma (NHL) [MIM:605027]: Cancer that starts in cells of the lymph system, which is part of the body's immune system. NHLs can occur at any age and are often marked by enlarged lymph nodes, fever and weight loss. {ECO:0000269|PubMed:14612909}. Note=The gene represented in this entry is involved in disease pathogenesis.; DISEASE: Cardiofaciocutaneous syndrome 1 (CFC1) [MIM:115150]: A multiple congenital anomaly disorder characterized by a distinctive facial appearance, heart defects and mental retardation. Heart defects include pulmonic stenosis, atrial septal defects and hypertrophic cardiomyopathy. Some affected individuals present with ectodermal abnormalities such as sparse, friable hair, hyperkeratotic skin lesions and a generalized ichthyosis-like condition. Typical facial features are similar to Noonan syndrome. They include high forehead with bitemporal constriction, hypoplastic supraorbital ridges, downslanting palpebral fissures, a depressed nasal bridge, and posteriorly angulated ears with prominent helices. {ECO:0000269|PubMed:16439621, ECO:0000269|PubMed:16474404, ECO:0000269|PubMed:18042262, ECO:0000269|PubMed:19206169}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Noonan syndrome 7 (NS7) [MIM:613706]: A form of Noonan syndrome, a disease characterized by short stature, facial dysmorphic features such as hypertelorism, a downward eyeslant and low-set posteriorly rotated ears, and a high incidence of congenital heart defects and hypertrophic cardiomyopathy. Other features can include a short neck with webbing or redundancy of skin, deafness, motor delay, variable intellectual deficits, multiple skeletal defects, cryptorchidism, and bleeding diathesis. Individuals with Noonan syndrome are at risk of juvenile myelomonocytic leukemia, a myeloproliferative disorder characterized by excessive production of myelomonocytic cells. {ECO:0000269|PubMed:19206169}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: LEOPARD syndrome 3 (LPRD3) [MIM:613707]: A disorder characterized by lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormalities of genitalia, retardation of growth, and sensorineural deafness. {ECO:0000269|PubMed:19206169}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=A chromosomal aberration involving BRAF is found in pilocytic astrocytomas. A tandem duplication of 2 Mb at 7q34 leads to the expression of a KIAA1549-BRAF fusion protein with a constitutive kinase activity and inducing cell transformation. {ECO:0000269|PubMed:18974108}.;
Intolerance Scores
- LoFtool
- 0.0212
- RVIS EVS
- -0.6
- RVIS percentile EVS
- 17.75
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- K
- Indispensability pred.
- E
- Indispensability score
- 0.853
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |