The BRAF c.1799T>G (p.Val600Gly, p.V600G) variant has been observed in somatic cancers, including 27 occurrences in COSMIC, and has been reported in ClinVar with a Pathogenic expert-panel classification from the ClinGen RASopathy Variant Curation Expert Panel.1 This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, supporting rarity in population reference datasets.2 In a published functional study, p.Val600Gly increased ERK and ELK phosphorylation relative to wild type, consistent with an activating effect; the BRAF RASopathy functional-study framework supports PS3 at supporting strength when one approved assay is available.3 Computational evidence supports a damaging missense effect, with REVEL 0.925 above the BRAF RASopathy PP3 threshold of 0.7, BayesDel 0.357299, and SpliceAI showing no major splice effect with a maximum delta score of 0.11.4
Final classification
Likely Pathogenic
PS3PM1PM2PM5PP3PP5
BRAF
c.1799T>G
p.Val600Gly
This variant
The BRAF c.1799T>G (p.Val600Gly, p.V600G) variant has been observed in somatic cancers, including 27 occurrences in COSMIC, and has been reported in ClinVar with a Pathogenic expert-panel classification from the ClinGen RASopathy Variant Curation Expert Panel.
ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRAF Version 2.3.0 v2.3.0 criteria-combination framework: matched Rule14 (2 Pathogenic.Moderate + Pathogenic.Supporting >=2) with applied criteria: PS3 supporting, PM1 moderate, PM2 supporting, PM5 moderate, PP3 supporting, PP5 supporting; maps to Likely Pathogenic.
Classification rationale
PS3PM1PM2PM5PP3PP5
Likely Pathogenic
BRAF c.1799T>G
PS3 + PM1 + PM2 + PM5 + PP3 + PP5
→
Likely Pathogenic
3
PMID:20735442 ↗cspec ↗vcep_svi_rasopathy_vcep_v2_approved_functional_studies
4
cspec ↗revelbayesdelspliceai ↗
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_001354609.1 · variants mapped to exon structure
BRAF
NM_001354609.1
Fetching transcript structure from UCSC…
Applied criteria · 6 applied · 12 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 6
Strength
Supporting
Moderate
Strong
Very strong
PS3
supporting
Pathogenic
In a published functional study, this variant increased ERK and ELK phosphorylation compared with wild type, consistent with an activating effect. Under the BRAF RASopathy specification, one approved functional assay supports PS3 at supporting strength.
PMID 20735442 functional analysis showed increased ERK and ELK phosphorylation versus wild typeRASopathy approved functional assay framework
PM1
moderate
Pathogenic
This missense change affects codon 600 within the BRAF CR3 activation segment (amino acids 594-627), a critical functional domain specified by the RASopathy framework. Published structural-functional data also support the importance of the activation segment in BRAF activation.
Codon 600 lies within the CSPEC-listed CR3 activation segment AA 594-627Published BRAF activation-segment mechanism data
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, meeting the RASopathy PM2 requirement that the variant be absent from controls.
Absent from gnomAD v2.1Absent from gnomAD v4.1
PM5
moderate
Pathogenic
Other missense substitutions affecting the same codon have been reported in ClinVar as likely pathogenic or pathogenic, including p.Val600Leu and p.Val600Met. This satisfies the BRAF same-residue comparator rule for PM5 at moderate strength.
ClinVar same-codon pathogenic/likely pathogenic comparators at Val600CSPEC PM5 same-residue rule
PP3
supporting
Pathogenic
Computational evidence supports a damaging missense effect. REVEL is 0.925, which is above the RASopathy PP3 threshold of 0.7; BayesDel is 0.357299; and SpliceAI predicts no significant splice impact with a maximum delta score of 0.11, which is consistent with this being primarily a missense effect rather than a splice-altering variant.
REVEL 0.925BayesDel 0.357299SpliceAI max delta 0.11
Assessed · not applied
· 3 not met · 9 not assessed
Pathogenic
PS2
A published report describes this variant as de novo in a patient with cardiofaciocutaneous syndrome, but the retrieved evidence does not document the parental confirmation details needed to assign PS2 points.
PS4
This variant has been observed in at least one published germline case and in somatic cancer databases, but the retrieved evidence does not provide the RASopathy point total or a case-control enrichment analysis needed to assign PS4.
PM6
A published de novo case was identified, but the retrieved evidence does not provide enough detail to determine whether the report should be scored as assumed de novo under the RASopathy PM6 point system.
PP1
No segregation data were identified for this variant, so PP1 cannot be applied.
PP2
This is a missense variant in a gene where missense disease is relevant, but the retrieved evidence did not provide the BRAF missense z score needed to determine whether the >3.09 threshold is met.
Benign
BA1
This variant is absent from gnomAD v2.1 and gnomAD v4.1 and does not meet the BA1 threshold of at least 0.05%.
BS1
This variant is absent from gnomAD v2.1 and gnomAD v4.1 and does not meet the BS1 threshold of at least 0.025%.
BS2
No observations in unaffected individuals were identified, so BS2 cannot be assessed.
BS4
No non-segregation data were identified for this variant, so BS4 cannot be applied.
BP2
No phase data or alternate molecular explanation in the same gene were identified, so BP2 cannot be assessed.
BP4
Available computational evidence does not support BP4.
BP5
No alternate molecular diagnosis or phenotype inconsistency evidence was identified, so BP5 cannot be assessed.
N/A · 10
PVS1 · PS1 · PM3 · PM4 · PP4 · BS3 · BP1 · BP3 · BP6 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory) and as Pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen RASopathy Variant Curation Expert Panel (expert panel). (ClinVarID = 40389)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.11). REVEL score = 0.925. BayesDel score = 0.357299.
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV56080151, n = 27 times).
Hotspots
This variant lies in a statistically significant hotspot.
Literature · how each cited paper was used
2papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 6 further PMIDs triaged but not cited — see Sources & references.
Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF.
Found
Structured finding pending for this record — see source link.
Applied to
→PM1
moderate
Germline mutation in BRAF codon 600 is compatible with human development: de novo p.V600G mutation identified in a patient with CFC syndrome.
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
supporting
Sources & reference links
Triaged references · 6 PMIDs not cited in assessment
28783719 ↗
Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS.
ONCOKB
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR