The BRAF c.1406G>A (p.Gly469Glu) variant has been observed in somatic cancers and has been reported in ClinVar with an expert panel pathogenic classification.1 This variant is absent from gnomAD v2.1 (0/251420 alleles), gnomAD v4.1 (0/1614020 alleles), and gnomAD-Canada, which supports rarity in population databases.2 In the RASopathy VCEP approved functional-study resource, p.Gly469Glu is listed as a pathogenic BRAF control in both MEK activation and ERK activation assays, and a published functional study showed constitutive ERK phosphorylation with low MEK phosphorylation, consistent with abnormal pathway activation.3 Computational data support a damaging missense effect, with REVEL 0.949 above the PP3 threshold, BayesDel 0.454064, and no predicted splice disruption by SpliceAI (max delta score 0.00).4
Final classification
VUS
PS3PM1PM2PP3PP5
BRAF
c.1406G>A
p.Gly469Glu
This variant
The BRAF c.1406G>A (p.Gly469Glu) variant has been observed in somatic cancers and has been reported in ClinVar with an expert panel pathogenic classification.
ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRAF Version 2.3.0 v2.3.0 criteria-combination framework was evaluated deterministically with applied criteria: PS3 moderate, PM1 moderate, PM2 supporting, PP3 supporting, PP5 supporting; no rule matched the adjudicated criteria.
Classification rationale
PS3PM1PM2PP3PP5
VUS
BRAF c.1406G>A
PS3 + PM1 + PM2 + PP3 + PP5
→
VUS
3
vcep_svi_rasopathy_vcep_v2_approved_functional_studiesPMID:18794803 ↗
4
revelbayesdelspliceai ↗cspec ↗
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 · 5 applied · 14 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 · 5
Strength
Supporting
Moderate
Strong
Very strong
PS3
moderate
review
Pathogenic
In the RASopathy VCEP approved functional-study resource, p.Gly469Glu is listed as a pathogenic BRAF control in both MEK activation and ERK activation assays, meeting the two-assay threshold for PS3_Moderate. In a published functional study, G469E-mutant melanoma cells showed constitutive ERK phosphorylation with low MEK phosphorylation, consistent with abnormal CRAF-dependent pathway activation.
Approved functional-study workbook lists G469E as pathogenic control in MEK activation assayApproved functional-study workbook lists G469E as pathogenic control in ERK activation assayPMID:18794803 reports constitutive pERK with low pMEK in G469E-mutant melanoma cells
PM1
moderate
review
Pathogenic
p.Gly469Glu lies in the BRAF P-loop (amino acids 459-474), which the BRAF RASopathy specification designates as a critical and well-established functional domain for PM1 at moderate strength.
CSPEC specifies the BRAF P-loop AA459-474 as PM1-eligibleResidue Gly469 falls within the P-loop
PM2
supporting
review
Pathogenic
This variant is absent from gnomAD v2.1 (0/251420 alleles) and gnomAD v4.1 (0/1614020 alleles), which meets the BRAF RASopathy PM2_Supporting requirement of absence from gnomAD. It is also absent from gnomAD-Canada.
gnomAD v2.1 total AC 0/251420gnomAD v4.1 total AC 0/1614020Absent from gnomAD-Canada
PP3
supporting
review
Pathogenic
For this missense variant, REVEL is 0.949, which is above the BRAF RASopathy PP3 threshold of 0.7. BayesDel is also positive at 0.454064, while SpliceAI shows no meaningful splice effect (max delta score 0.00), supporting a pathogenic missense effect rather than a splice-driven mechanism.
REVEL 0.949BayesDel 0.454064SpliceAI max delta 0.00
Assessed · not applied
· 3 not met · 11 not assessed
Pathogenic
PS1
No previously established pathogenic variant producing the same amino acid change by a different nucleotide change, or a verified analogous RAF1/BRAF residue match, was confirmed in the inspected evidence.
PS2
Published CFC data indicate that BRAF-related cases are often de novo, but confirmed de novo status with the point-based PS2 evidence required for this specific variant was not verified from the inspected evidence.
PS4
This variant has been reported clinically, but the exact number of unrelated affected individuals and the RASopathy VCEP point-based PS4 score were not verified from the inspected evidence.
PM5
The BRAF RASopathy framework uses classic same-residue PM5 logic, but no verified same-codon pathogenic comparator was confirmed from the inspected evidence for this review.
PM6
A sporadic or assumed de novo occurrence for this exact variant was not verified well enough to assign PM6 under the point-based RASopathy framework.
PP1
No segregation data were identified that establish co-segregation of this variant with disease across the informative meioses required by the RASopathy framework.
PP2
The BRAF RASopathy specification allows PP2 when the missense z score is greater than 3.09, but a missense constraint z score was not verified in the inspected evidence.
Benign
BA1
This variant does not meet BA1 because it is absent from gnomAD v2.1 and gnomAD v4.1, which is below the BRAF RASopathy BA1 threshold of 0.05%.
BS1
This variant does not meet BS1 because it is absent from gnomAD v2.1 and gnomAD v4.1, which is below the BRAF RASopathy BS1 threshold of 0.025%.
BS2
No observations in unaffected individuals were identified to support BS2 under the RASopathy point-based framework.
BS4
No non-segregation evidence was identified for this variant, so BS4 cannot be assessed.
BP2
No phase data were identified showing this variant in trans with a pathogenic variant for a fully penetrant dominant disorder or in cis with another established pathogenic variant.
BP4
This missense variant does not meet BP4 because REVEL is 0.949, which is above the benign-supporting threshold of 0.3.
BP5
No alternate molecular explanation with the point-based evidence required for BP5 was identified.
N/A · 9
PVS1 · PM3 · PM4 · PP4 · BS3 · BP1 · BP3 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1614020 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/75050 alleles, homozygotes = 0).
v2.1
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/251420 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16256 alleles, homozygotes = 0).
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / 1,614,020
0 hom
0 hom
Not observed in any ancestry group.
+ 10 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))
gnomAD v2.1
Absent
· 0 / 251,420
0 hom
0 hom
Not observed in any ancestry group.
+ 8 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Pathogenic (14 clinical laboratories) and as Pathogenic by ClinGen RASopathy Variant Curation Expert Panel (expert panel). (ClinVarID = 13974)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.949. BayesDel score = 0.454064.
Functional
Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: 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; COSV56065622, n = 36 times).
Hotspots
This variant lies in a statistically significant hotspot.
Literature · how each cited paper was used
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 5 further PMIDs triaged but not cited — see Sources & references.
CRAF inhibition induces apoptosis in melanoma cells with non-V600E BRAF mutations.
Found
Approved functional-study workbook lists G469E as pathogenic control in MEK activation assay Approved functional-study workbook lists G469E as pathogenic control in ERK activation assay PMID:18794803 reports constitutive pERK with low pMEK in G469E-mutant melanoma cells
Applied to
→PS3
moderate
Sources & reference links
9Sources
Triaged references · 5 PMIDs not cited in assessment
15035987 ↗
Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF.
ONCOKB
16439621 ↗
Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome.
ONCOKB
28783719 ↗
Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS.
ONCOKB
15150094 ↗
Different effects of point mutations within the B-Raf glycine-rich loop in colorectal tumors on mitogen-activated protein/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase and nuclear factor kappaB pathway and cellular transformation.
ONCOKB
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR