About BRAF
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRAF c.1406G>A, p.(Gly469Glu)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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.
01The reasoning
How it was classified
The recorded framework is ClinGen BRAF VCEP v2.3.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 5
Benign evidence criteria: 0
Pathogenic criteria applied · 5
PS3Moderate
PS3 · moderate
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.
PM1Moderate
PM1 · moderate
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.
PM2Supporting
PM2 · supporting
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.
PP3Supporting
PP3 · supporting
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.
PP5Supporting
PP5 · supporting
Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Pathogenic.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
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.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
0 / 1,614,020 alleles
gnomAD v4.1: 0 / 1,614,020 alleles. Recorded AF 0. Recorded homozygote count 0.
gnomAD 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).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
14 reported laboratory submissions
14 Pathogenic.
Functional evidence
Statement recorded
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
36 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV56065622, n = 36 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen BRAF VCEP v2.3.0, with the data and sources behind each one.
28 criteria with recorded statuses: 5 met · 3 not met · 11 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
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.
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.
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).
No criteria match.
Met · 5
PS3 ModerateIn 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. Details ▾Hide ▴
Rule
PS3 Moderate: two or more different approved assays
Evidence considered
- 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
Still missing
- Direct full-text review of all underlying assay figures would further confirm assay-level details.
Sources
PM1 Moderatep.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. Details ▾Hide ▴
Rule
PM1 Moderate for exon 6, exon 11, P-loop (AA459-474), or CR3 activation segment (AA594-627)
Evidence considered
- CSPEC specifies the BRAF P-loop AA459-474 as PM1-eligible
- Residue Gly469 falls within the P-loop
Sources
PM2 SupportingThis 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. Details ▾Hide ▴
Rule
PM2 Supporting: variant absent from controls (gnomAD)
Evidence considered
- gnomAD v2.1 total AC 0/251420
- gnomAD v4.1 total AC 0/1614020
- Absent from gnomAD-Canada
Sources
PP3 SupportingFor 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. Details ▾Hide ▴
Rule
PP3 Supporting for missense variants with REVEL >=0.7
Evidence considered
- REVEL 0.949
- BayesDel 0.454064
- SpliceAI max delta 0.00
Sources
Not met · 3 · evaluated, threshold not reached
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%. Details ▾Hide ▴
Rule
BA1 if gnomAD filtering allele frequency >=0.05%
Evidence considered
- gnomAD v2.1 AF 0.00000%
- gnomAD v4.1 AF 0.00000%
- BA1 threshold 0.05%
Sources
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%. Details ▾Hide ▴
Rule
BS1 if gnomAD filtering allele frequency >=0.025%
Evidence considered
- gnomAD v2.1 AF 0.00000%
- gnomAD v4.1 AF 0.00000%
- BS1 threshold 0.025%
Sources
BP4 This missense variant does not meet BP4 because REVEL is 0.949, which is above the benign-supporting threshold of 0.3. SpliceAI predicts no significant splice impact (max delta score 0.00), but the missense prediction profile does not support a benign interpretation. Details ▾Hide ▴
Rule
BP4 Supporting for missense variants with REVEL <=0.3
Evidence considered
- REVEL 0.949
- BP4 threshold REVEL <=0.3
- SpliceAI max delta 0.00
- BayesDel 0.454064
Sources
Not assessed · 11 · no assessment recorded
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. Details ▾Hide ▴
Rule
Same amino acid change as previously established pathogenic variant; analogous BRAF/RAF1 residues allowed
Evidence considered
- CSPEC allows PS1 for same amino acid change and analogous BRAF/RAF1 residues
- RAF alignment file was inspected without a confirmed applicable comparator
Still missing
- A verified same-amino-acid alternate-nucleotide comparator was not identified.
- No confirmed analogous RAF1 residue evidence was extracted for this variant.
Sources
cspec ↗vcep_raf_alignment
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. Details ▾Hide ▴
Rule
PS2 point-based framework
Evidence considered
- RASopathy CSPEC uses a point-based PS2 framework
- PMID:16439621 reports de novo missense mutations in BRAF-associated CFC
- ClinVar shows expert panel and multiple clinical submissions but not the required PS2 point details
Still missing
- Case-level confirmation that this exact variant occurred de novo was not verified.
- Parentage confirmation and PS2 point assignment were not established.
Sources
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. Details ▾Hide ▴
Rule
PS4 point-based framework
Evidence considered
- RASopathy CSPEC uses a point-based PS4 framework
- ClinVar shows expert panel review and multiple pathogenic submissions
Still missing
- Unrelated affected case count was not confirmed.
- PS4 point total was not established.
- Case de-duplication across reports was not verified.
Sources
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. Details ▾Hide ▴
Rule
PM5 Moderate for one pathogenic/likely pathogenic residue change at the same codon; Strong for qualifying multiple changes/probands
Evidence considered
- CSPEC permits classic same-residue PM5
- PM5 candidate artifact did not yield a confirmed usable comparator
Still missing
- A confirmed same-residue pathogenic or likely pathogenic comparator was not verified.
- The harvested PM5 artifact did not provide an adjudicated comparator for use.
Sources
cspec ↗pm5_candidates
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. Details ▾Hide ▴
Rule
PM6 point-based framework
Evidence considered
- RASopathy CSPEC uses a point-based PM6 framework
- Published CFC studies support de novo occurrence at the gene-disease level but not a verified PM6 score for this exact variant in the inspected evidence
Still missing
- Case-level inheritance wording for this exact variant was not verified.
- PM6 point total was not established.
Sources
PP1 No segregation data were identified that establish co-segregation of this variant with disease across the informative meioses required by the RASopathy framework. Details ▾Hide ▴
Rule
PP1 Supporting/Moderate/Strong based on informative meioses
Evidence considered
- No verified segregation dataset was identified
Still missing
- No informative meioses were verified for this variant.
Sources
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. Details ▾Hide ▴
Rule
PP2 Supporting if missense z score >3.09 in gnomAD
Evidence considered
- CSPEC uses missense z score >3.09 for PP2
Still missing
- Missense z score for BRAF was not retrieved from the inspected materials.
Sources
BS2 No observations in unaffected individuals were identified to support BS2 under the RASopathy point-based framework. Details ▾Hide ▴
Rule
BS2 point-based framework
Evidence considered
- No BS2 point-bearing observations were identified
Still missing
- No unaffected carrier data were verified.
Sources
BS4 No non-segregation evidence was identified for this variant, so BS4 cannot be assessed. Details ▾Hide ▴
Rule
BS4 requires informative non-segregation
Evidence considered
- No verified family non-segregation data were identified
Still missing
- No informative non-segregation data were verified.
Sources
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. Details ▾Hide ▴
Rule
BP2 point-based framework
Evidence considered
- No BP2 point-bearing phase data were identified
Still missing
- No cis/trans phase observations were verified.
Sources
BP5 No alternate molecular explanation with the point-based evidence required for BP5 was identified. Details ▾Hide ▴
Rule
BP5 point-based framework
Evidence considered
- No BP5-supporting dataset was identified
Still missing
- No verified BP5 point-bearing alternate diagnosis data were identified.
Sources
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 VCEPThis is a missense variant, and the BRAF RASopathy specification marks PVS1 as not applicable. The generic PVS1 scaffold also indicates that this variant does not fall into a null-variant category. Details ▾Hide ▴
VCEP rule
BRAF RASopathy VCEP: PVS1 not applicable
Evidence considered
- BRAF CSPEC lists PVS1 as not applicable
- Generic PVS1 scaffold does not place c.1406G>A in a null-variant bucket
Sources
PM3 VCEPThe BRAF RASopathy specification marks PM3 as not applicable for this gene-disease context. Details ▾Hide ▴
VCEP rule
BRAF RASopathy VCEP: PM3 not applicable
Evidence considered
- CSPEC lists PM3 as not applicable
Sources
PM4 N/AThis is a missense substitution and does not change protein length, so PM4 is not applicable. Details ▾Hide ▴
Rule
PM4 for protein length changes outside repetitive regions
Evidence considered
- Variant is a missense substitution
- not an in-frame insertion/deletion or stop-loss
Sources
PP4 VCEPThe BRAF RASopathy specification marks PP4 as not applicable. Details ▾Hide ▴
VCEP rule
BRAF RASopathy VCEP: PP4 not applicable
Evidence considered
- CSPEC lists PP4 as not applicable
Sources
BS3 VCEPThe BRAF RASopathy specification marks BS3 as not applicable. Details ▾Hide ▴
VCEP rule
BRAF RASopathy VCEP: BS3 not applicable
Evidence considered
- CSPEC lists BS3 as not applicable
Sources
BP1 N/AIn the BRAF RASopathy framework, BP1 is adapted for truncating variants in a gain-of-function disease context. This variant is missense, so BP1 is not applicable. Details ▾Hide ▴
Rule
BP1 Supporting for truncating variants in genes without established LOF correlation to disease
Evidence considered
- Variant is missense
- CSPEC adapts BP1 for truncating variants in this gene-disease setting
Sources
BP3 VCEPThe BRAF RASopathy specification marks BP3 as not applicable. Details ▾Hide ▴
VCEP rule
BRAF RASopathy VCEP: BP3 not applicable
Evidence considered
- CSPEC lists BP3 as not applicable
Sources
BP6 VCEPThe BRAF RASopathy specification marks BP6 as not applicable. Details ▾Hide ▴
VCEP rule
BRAF RASopathy VCEP: BP6 not applicable
Evidence considered
- CSPEC lists BP6 as not applicable
Sources
BP7 N/AThis is not a synonymous or non-coding splice-region variant, so BP7 is not applicable. Details ▾Hide ▴
Rule
BP7 for synonymous or eligible intronic/non-coding variants with no predicted splice effect
Evidence considered
- Variant is missense
- BP7 applies to synonymous or relevant intronic/non-coding variants
Sources
Identifiers
- Gene
- BRAF
- Transcript
- NM_001354609.1
- Coding (HGVS c.)
- NM_001354609.1:c.1406G>A
- Protein (HGVS p.)
- NP_001341538.1:p.(Gly469Glu)
- GRCh38
- chr7:140781602 C>T
- GRCh37
- chr7:140481402 C>T
- ClinVar
- 376073, 13974
- COSMIC
- COSV56065622
Gene diagram
Every interpreted variant in BRAF, mapped onto the exon structure of NM_001354609.1. Select a row to find it on the plot.
BRAFNM_001354609.1
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in BRAF
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
0 / 1,614,020 alleles
AF 0 · 0 homozygotes
gnomAD v2.1
0 / 251,420 alleles
AF 0 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 0 · 0 / 1,614,020 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.
gnomAD v2.1
AF 0 · 0 / 251,420 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.
Statements
gnomAD 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).
gnomAD 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).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.949
- BayesDel
- 0.454
How the predictions were used
PP3 SupportingFor 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. Details ▾Hide ▴
Rule
PP3 Supporting for missense variants with REVEL >=0.7
Evidence considered
- REVEL 0.949
- BayesDel 0.454064
- SpliceAI max delta 0.00
Sources
BP4 This missense variant does not meet BP4 because REVEL is 0.949, which is above the benign-supporting threshold of 0.3. SpliceAI predicts no significant splice impact (max delta score 0.00), but the missense prediction profile does not support a benign interpretation. Details ▾Hide ▴
Rule
BP4 Supporting for missense variants with REVEL <=0.3
Evidence considered
- REVEL 0.949
- BP4 threshold REVEL <=0.3
- SpliceAI max delta 0.00
- BayesDel 0.454064
Sources
BP7 N/AThis is not a synonymous or non-coding splice-region variant, so BP7 is not applicable. Details ▾Hide ▴
Rule
BP7 for synonymous or eligible intronic/non-coding variants with no predicted splice effect
Evidence considered
- Variant is missense
- BP7 applies to synonymous or relevant intronic/non-coding variants
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.949. BayesDel score = 0.454064.
6 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
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PMID 15035987 ↗Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF.Wan PT et al. · 2004No paper-specific finding is recorded.
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PMID 16439621 ↗Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome.Rodriguez-Viciana P et al. · 2006No paper-specific finding is recorded.
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PMID 18794803 ↗CRAF inhibition induces apoptosis in melanoma cells with non-V600E BRAF mutations.Smalley KS et al. · 2009No paper-specific finding is recorded.
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PMID 28783719 ↗Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS.No paper-specific finding is recorded.
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PMID 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.No paper-specific finding is recorded.
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
0 / 1,614,020 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
14 Pathogenic
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/643243119
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/13974/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/7-140481402-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr7-140781602-C-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/7-140781602-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001354609.1%3Ac.1…
- OncoKB ↗www.oncokb.org/gene/BRAF/G469E
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=221405913
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD 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).
gnomAD 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).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
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
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Oncogenic.
Somatic
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV56065622, n = 36 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.