BRAF

Chr 7AD

B-Raf proto-oncogene, serine/threonine kinase

Also known as: B-RAF1, B-raf, BRAF-1, BRAF1, NS7, RAFB1

NCBI Gene: 673 ENSG00000157764 UniProt: P15056 OMIM: 164757

BRAF encodes a serine/threonine protein kinase that regulates the MAP kinase/ERK signaling pathway controlling cell division, differentiation, and secretion. Loss-of-function mutations cause autosomal dominant cardiofaciocutaneous syndrome, Noonan syndrome 7, and LEOPARD syndrome 3, which present with overlapping phenotypes including developmental delays, cardiac abnormalities, and distinctive facial features. The gene is extremely intolerant to loss-of-function variation, indicating that haploinsufficiency is the likely pathogenic mechanism in these developmental disorders.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Adenocarcinoma of lung, somaticMIM #211980

Cardiofaciocutaneous syndromeMIM #115150

Colorectal cancer, somaticMIM #114500

LEOPARD syndrome 3MIM #613707

Melanoma, malignant, somaticMIM #155600

Nonsmall cell lung cancer, somaticMIM #211980

Noonan syndrome 7MIM #613706

UniProtFamilial non-Hodgkin lymphoma

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · cardiofaciocutaneous syndrome · AD · ClinGen 2018
Definitive · cardiofaciocutaneous syndrome 1 · AD · Ambry Genetics
Definitive · LEOPARD syndrome 3 · AD · G2P
Definitive · Noonan syndrome 7 · AD · G2P
Limited · Noonan syndrome with multiple lentigines · AD · ClinGen 2018 — not for standalone diagnostic reporting
Limited · anaplastic astrocytoma · AD · Ambry Genetics — not for standalone diagnostic reporting
Disputed · Costello syndrome · AD · ClinGen 2018 — evidence questions this relationship

+2 more curated pairs

Interpreting a novel variant

Gain of function is the curated mechanism (Gene2Phenotype), so a variant that simply removes the protein may not be the pathogenic class here — missense variants in functional domains often carry more weight.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

3778

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.21

LOEUF· LoF intol.

GOF*

Mechanism· G2P

📖

GeneReview available — BRAF

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.21LOEUF

pLI 1.000

Z-score 5.91

OE 0.10 (0.05–0.21)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

3.72Z-score

OE missense 0.49 (0.43–0.55)

203 obs / 416.7 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.10 (0.05–0.21)

0≤0.351.4

Missense OE?0.49 (0.43–0.55)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 5 / 50.2Missense obs/exp: 203 / 416.7Syn Z: -0.22

Background carrier burden — how many people carry a rare variant somewhere in BRAF?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 140

625 rare PASS variants

Rare truncating (LoF)

1 in 8,400

30 rare PASS variants

Rare synonymous (reference)

1 in 120

348 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for BRAF. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 230	1 in 8,900
South Asian	~43k	1 in 98	≈ 1 in 22,000
Remaining (unassigned)	~30k	1 in 190	≈ 1 in 30,000
European (Finnish)	~27k	1 in 500	1 in 5,300
Admixed American	~22k	1 in 200	≈ 1 in 22,000
African / African American	~21k	1 in 160	≈ 1 in 9,200
East Asian	~20k	1 in 160	1 in 2,300
Ashkenazi Jewish	~13k	1 in 450	none seen
Middle Eastern	~2,884	1 in 140	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 16 of 20 coding exons well covered in gnomAD exomes; exon 10 poorly covered; exons 1, 2, 16 marginal. Genomes: 19 of 20 (exon 19 below).? see exons ↓

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

BRAF · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

VCEP specificationsRASopathyReleased

Specifications ↗Panel ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

📖

GeneReview available — BRAF

Authoritative clinical overview · NCBI Bookshelf · Recommended first read

Open GeneReview ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

MelanomaNon-Small-Cell Lung CancerThyroid Cancer

A Study to Learn About the Study Medicine Called PF-07799933 in People With Advanced Solid Tumors With BRAF Alterations.

ACTIVE NOT RECRUITING

NCT05355701Phase PHASE1PfizerStarted 2022-07-05

PF-07799933binimetinibcetuximab

Haematological MalignancySolid Tumour

DETERMINE (Determining Extended Therapeutic Indications for Existing Drugs in Rare Molecularly Defined Indications Using a National Evaluation Platform Trial) - Master Screening Protocol

RECRUITING

NCT05722886Phase PHASE2, PHASE3Cancer Research UKStarted 2023-03-01

AlectinibAtezolizumabEntrectinib

OncologyMEK MutationRAF Gene Mutation

A Study to Investigate the Safety and Efficacy of NST-628 Oral Tablets in Subjects With Solid Tumors

RECRUITING

NCT06326411Phase PHASE1Nested Therapeutics, IncStarted 2024-04-09

NST-628

Non-Small Cell Lung Cancer

Observational Prospective Study of Quality of Life in Unresectable TNM Stage III NSCLC (OBSTINATE)

ACTIVE NOT RECRUITING

NCT05049044Groupe Francais De Pneumo-CancerologieStarted 2020-12-18