BRAF c.1799T>A, p.Val600Glu
NM_004333.4:c.1799T>A
COSM476
Population Frequency
0.000398%
Rare
ClinVar Classification
Likely Pathogenic
5 publications
REVEL Score
0.931
Likely Pathogenic
COSMIC Recurrence
30635 occurrences
PM1 Criterion Applied
Classification Evidence
Detailed Information
Genetic Information
Gene & Transcript Details
Gene
BRAF
Transcript
NM_004333.6
MANE Select
Total Exons
18
Strand
Reverse (−)
Reference Sequence
NC_000007.13
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_004333.5 | RefSeq Select | 18 exons | Reverse |
| NM_004333.3 | Alternative | 18 exons | Reverse |
| NM_004333.4 | Alternative | 18 exons | Reverse |
| NM_004333.2 | Alternative | 18 exons | Reverse |
Variant Details
HGVS Notation
NM_004333.4:c.1799T>A
Protein Change
V600E
Location
Exon 15
(Exon 15 of 18)
5'
Exon Structure (18 total)
3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 600: V600G, V600L, V600L, V600M
Alternate Identifiers
COSM476
Variant interpretation based on transcript NM_004333.6
Clinical Evidence
Global Frequency
0.000398%
Extremely Rare
Highest in Population
South Asian
0.00327%
Rare
Global: 0.000398%
South Asian: 0.00327%
0%
0.0005%
0.001%
0.01%
0.05%
1%+
Allele Information
Total: 251260
Alt: 1
Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.000398%, 1/251260 alleles, homozygotes = 0) and at a higher frequency in the South Asian population (MAF= 0.00327%, 1/30612 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
5 publications
Likely Pathogenic
Based on 10 submitter reviews in ClinVar
Submitter Breakdown
Pathogenic
Likely Pathogenic
VUS
Likely Benign
Benign
Publications
5 publications
Show publication details
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (6 clinical laboratories) and as Likely pathogenic (2 clinical laboratories) and as Uncertain significance (2 clinical laboratories).
Functional Domain
Hotspot Status
Hotspot
PM1
Mutation Count
5382
Reported mutations in this domain
0
50
100+
Domain Summary
This variant is located in a mutational hotspot or critical domain (5382 mutations).
PM1 criterion applied: Located in a mutational hot spot and/or critical and well-established functional domain.
Related Variants in This Domain
ClinVar reports other pathogenic variants at position 600: V600G, V600L, V600L, V600M
PM5 criterion applied: Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
Functional Studies
Summary
Gain-of-Function Mutation
The BRAF V600E variant has been functionally characterized as a gain-of-function mutation. It is located in the kinase domain of the BRAF protein and leads to constitutive activation of the kinase. This mutation activates the downstream MAPK pathway independently of RAS, increases BRAF kinase activity, enhances downstream signaling, and has the ability to transform cells in culture. Additionally, it retains sensitivity to RAF monomer inhibitors such as vemurafenib and dabrafenib.
Computational Evidence
Pathogenicity Predictions
REVEL Score
0.931
0.931
Likely Benign
0.0
Uncertain (Low)
0.2
Uncertain (Med)
0.5
Likely Pathogenic
0.75
REVEL scores ≥ 0.75 are considered strong evidence of pathogenicity (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
Yes
Additional Predictors
Pathogenic:
polyphen_prediction: probably_damaging
mutationtaster: D
primateai: D
Benign:
CADD: 5.51
metasvm: T
metalr: T
Neutral:
Show all
VCEP Guidelines
Applied ACMG/AMP Criteria
RASopathy VCEP
PVS1
PVS1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PVS1 is: "Null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss-of-function is a known mechanism of disease." The evidence for this variant shows: NM_004333.4:c.1799T>A is a missense change (p.V600E) in BRAF, which causes gain-of-function, not loss-of-function. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PS1 is: "Strong Strength: Same amino acid change as a previously established pathogenic variant regardless of nucleotide change." The evidence for this variant shows: p.V600E is the canonical nucleotide change (c.1799T>A) and no alternate nucleotide change producing the same amino acid has been established. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." The evidence for this variant shows: no de novo occurrence data provided. Therefore, this criterion is not applied.
PS3
PS3 (Moderate)
Strength Modified
According to VCEP guidelines, the rule for PS3 is: "Moderate Strength: Two or more different approved assays." The evidence for this variant shows: multiple well-established functional studies demonstrate that BRAF V600E is a gain-of-function mutation activating the MAPK pathway, increases kinase activity, transforms cells, and retains inhibitor sensitivity. Therefore, this criterion is applied at Moderate strength.
PS4
PS4 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PS4 is: "Strong Strength: ≥5 points; Moderate Strength: ≥3 points; Supporting Strength: ≥1 point from case-control or proband data." The evidence for this variant shows: no quantitative case-control or number-of-probands data provided. Therefore, this criterion is not applied.
PM1
PM1 (Moderate)
According to VCEP guidelines, the rule for PM1 is: "Moderate Strength: Applicable only to critical and well-established functional domains (exon 6, exon 11, P-loop [AA 459-474], CR3 activation segment [AA 594-627])." The evidence for this variant shows: p.V600E resides within the CR3 activation segment (AA 594-627) of the BRAF kinase domain. Therefore, this criterion is applied at Moderate strength.
PM2
PM2 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Supporting Strength: The variant must be absent from controls (gnomAD)." The evidence for this variant shows: present in gnomAD at MAF=0.000398%. Therefore, this criterion is not applied.
PM3
PM3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "For recessive disorders, detected in trans with a pathogenic variant." The evidence for this variant shows: not relevant for BRAF gain-of-function. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions." The evidence for this variant shows: it is a missense change, not an in-frame indel. Therefore, this criterion is not applied.
PM5
PM5 (Moderate)
According to VCEP guidelines, the rule for PM5 is: "Moderate Strength: One [likely] pathogenic residue change at the same codon." The evidence for this variant shows: other missense changes at codon 600 (e.g., V600K, V600D) have been established as pathogenic. Therefore, this criterion is applied at Moderate strength.
PM6
PM6 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity." The evidence for this variant shows: no de novo data provided. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: "Co-segregation with disease in multiple affected family members." The evidence for this variant shows: no segregation data provided. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PP2 is: "Supporting Strength: Missense z score >3.09 in gnomAD." The evidence for this variant shows: no missense constraint score provided. Therefore, this criterion is not applied.
PP3
PP3 (Supporting)
According to VCEP guidelines, the rule for PP3 is: "Supporting Strength: For missense variants, REVEL ≥0.7." The evidence for this variant shows: REVEL score is 0.93. Therefore, this criterion is applied at Supporting strength.
PP4
PP4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology." The evidence for this variant shows: no germline phenotype information provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic, but evidence not available." The evidence for this variant shows: ClinVar submissions vary (Pathogenic, Likely Pathogenic, VUS), and VCEP guidelines recommend against applying PP5. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Stand Alone Strength: GnomAD filtering allele frequency ≥0.05%." The evidence for this variant shows: MAF=0.000398%, below threshold. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Strong Strength: GnomAD filtering allele frequency ≥0.025%." The evidence for this variant shows: MAF=0.000398%, below threshold. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: "Observed in a healthy adult with full penetrance expected at an early age." The evidence for this variant shows: no healthy adult data provided. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: "Well-established in vitro or in vivo functional studies show no damaging effect." The evidence for this variant shows: functional studies demonstrate damaging gain-of-function. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected members of a family." The evidence for this variant shows: no segregation data provided. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BP1 is: "Supporting Strength: Truncating variant in gene where only gain-of-function is disease mechanism." The evidence for this variant shows: this is a missense gain-of-function variant. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for a fully penetrant dominant gene." The evidence for this variant shows: no trans observation data. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in repetitive regions without a known function." The evidence for this variant shows: it is a missense change, not an in-frame indel. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BP4 is: "Supporting Strength: For missense variants, REVEL ≤0.3." The evidence for this variant shows: REVEL=0.93, above threshold. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease." The evidence for this variant shows: no such data provided. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign, but evidence not available." The evidence for this variant shows: no reputable benign reports. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "Silent variant with no predicted splicing impact and nucleotide not highly conserved." The evidence for this variant shows: it is a missense variant. Therefore, this criterion is not applied.