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

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]

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

1612

ClinVar variants

Pathogenic / LP

1.00

pLI score· haploinsufficient

Active trials

Clinical Summary— BRAF

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

13 Pathogenic / Likely Pathogenic· 230 VUS of 1612 total submissions

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Clinical Trials

12 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

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?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.10 (0.05–0.21)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.49 (0.43–0.55)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.02

0≤1.21.6

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

ClinVar Variant Classifications

1612 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic8

Likely Pathogenic5

VUS230

Likely Benign212

Benign4

Conflicting5

Pathogenic

Likely Pathogenic

230

VUS

212

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	2	6	0	8
Likely Pathogenic	0	5	0	0	5
VUS	13	177	32	8	230
Likely Benign	2	4	82	124	212
Benign	0	0	3	1	4
Conflicting	—				5
Total	15	188	123	133	464

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in 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.

Gene2Phenotype Curations

BRAF-related Noonan syndrome

definitive

ADGain Of FunctionAltered Gene Product Structure

Skin

G2P ↗

BRAF-related LEOPARD syndrome

definitive

ADGain Of FunctionAltered Gene Product Structure

Skin

G2P ↗

BRAF-related cardiofaciocutaneous syndrome

definitive

ADGain Of FunctionAltered Gene Product Structure

Dev. DisordersSkin

G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

B-RAF PROTOONCOGENE, SERINE/THREONINE KINASE; BRAF

MIM #164757 · *

Adenocarcinoma of lung, somatic

MIM #211980