About BRAF
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRAF c.1796C>G, p.(Thr599Arg)
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: 4
Benign evidence criteria: 0
Pathogenic criteria applied · 4
PS3Moderate
PS3 · moderate
In approved functional studies, this variant was listed as pathogenic in both MEK activation and ERK activation assays, consistent with abnormal downstream MAPK pathway activation. Under the BRAF RASopathy specification, results from 2 different approved assays meet PS3 at Moderate strength.
PM1Moderate
PM1 · moderate
Thr599 lies within the BRAF CR3 activation segment (amino acids 594-627), which the BRAF RASopathy specification defines as a critical and well-established functional region for PM1.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and gnomAD v4.1. Under the BRAF RASopathy specification, absence from controls supports PM2 at Supporting strength.
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, 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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
No listed criterion applied
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
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
Not assessed
No COSMIC evidence statement is recorded in this case.
Cancer Hotspots
This variant does not lie 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: 4 met · 4 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.1796C>G (p.Thr599Arg) variant has been reported in ClinVar as pathogenic, including an expert panel pathogenic classification, and is also represented in curated cancer variant resources.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports rarity in population reference datasets.
In approved functional studies, this variant was classified as pathogenic in both MEK activation and ERK activation assays, supporting abnormal MAPK pathway signaling consistent with the disease mechanism.
In silico evidence does not meet the BRAF RASopathy thresholds for PP3 or BP4 because REVEL is 0.359, SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, and BayesDel is 0.308415.
No criteria match.
Met · 4
PS3 ModerateIn approved functional studies, this variant was listed as pathogenic in both MEK activation and ERK activation assays, consistent with abnormal downstream MAPK pathway activation. Under the BRAF RASopathy specification, results from 2 different approved assays meet PS3 at Moderate strength. Details ▾Hide ▴
Rule
Two or more different approved assays
Evidence considered
- Approved MEK activation assay lists T599R as P
- Approved ERK activation assay lists T599R as P
Sources
PM1 ModerateThr599 lies within the BRAF CR3 activation segment (amino acids 594-627), which the BRAF RASopathy specification defines as a critical and well-established functional region for PM1. Details ▾Hide ▴
Rule
Applicable to critical and well-established functional domains including CR3 activation segment (AA 594-627)
Evidence considered
- BRAF-specific PM1 region includes the CR3 activation segment aa 594-627
- Variant protein consequence is p.Thr599Arg
Sources
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1. Under the BRAF RASopathy specification, absence from controls supports PM2 at Supporting strength. Details ▾Hide ▴
Rule
The variant must be absent from controls (gnomAD)
Evidence considered
- gnomAD v2.1 absent
- gnomAD v4.1 absent
Sources
Not met · 4 · evaluated, threshold not reached
PP3 Computational evidence does not meet the BRAF RASopathy threshold for PP3. REVEL is 0.359, which is below the required threshold of 0.7, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00. BayesDel is 0.308415, but this does not change the VCEP missense rule application. Details ▾Hide ▴
Rule
For missense variants: REVEL ≥0.7; for splicing impact, predicted outcome must match disease mechanism
Evidence considered
- REVEL 0.359
- SpliceAI max delta 0.00
- BayesDel 0.308415
Sources
BA1 This variant does not meet BA1 because it is absent from gnomAD and therefore is below the BRAF RASopathy filtering allele frequency threshold of 0.05%. Details ▾Hide ▴
Rule
GnomAD filtering allele frequency ≥0.05%
Evidence considered
- gnomAD v2.1 absent
- gnomAD v4.1 absent
Sources
BS1 This variant does not meet BS1 because it is absent from gnomAD and therefore is below the BRAF RASopathy filtering allele frequency threshold of 0.025%. Details ▾Hide ▴
Rule
GnomAD filtering allele frequency ≥0.025%
Evidence considered
- gnomAD v2.1 absent
- gnomAD v4.1 absent
Sources
BP4 Computational evidence does not meet the BRAF RASopathy threshold for BP4. REVEL is 0.359, which is above the benign threshold of 0.3, although SpliceAI predicts no significant splice impact with a maximum delta score of 0.00. BayesDel is 0.308415, but the VCEP missense rule is not met. Details ▾Hide ▴
Rule
For missense variants: REVEL ≤0.3
Evidence considered
- REVEL 0.359
- SpliceAI max delta 0.00
- BayesDel 0.308415
Sources
Not assessed · 11 · no assessment recorded
PS1 No directly reviewed evidence established that this same amino acid change has already been classified as pathogenic from an independent nucleotide change or from an approved analogous RAF position analysis. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic variant; applicable to analogous BRAF and RAF1 positions
Evidence considered
- BRAF RASopathy specification allows PS1 for same amino acid changes including analogous RAF positions
Still missing
- Direct codon-level review for the same amino acid change from a different nucleotide change
- Direct review of analogous RAF-position evidence if used
Sources
cspec ↗vcep_raf_alignment
PS2 No confirmed de novo occurrence with the point threshold required by the BRAF RASopathy specification was directly established from the reviewed evidence. Details ▾Hide ▴
Rule
Point-based de novo scoring: 4 points very strong, 2 strong, 1 moderate
Evidence considered
- RASopathy specification uses a point-based de novo framework
- Available literature pointers did not provide a directly verified de novo point total for this variant
Still missing
- Case-level parental testing details
- Confirmed or assumed de novo point count
Sources
PS4 Affected-case enrichment meeting the RASopathy point threshold was not directly established from the reviewed evidence, so PS4 was not applied. Details ▾Hide ▴
Rule
Point-based prevalence in affected individuals: 5 points strong, 3 moderate, 1 supporting
Evidence considered
- ClinVar contains pathogenic submissions including expert panel review
- Reviewed sources did not provide a directly confirmed PS4 point total
Still missing
- Verified count of unrelated affected probands with this exact variant
- Case-level point total under the RASopathy framework
Sources
PM5 No directly reviewed codon-level evidence established a different pathogenic missense change at this same codon at the strength required by the BRAF RASopathy specification. Details ▾Hide ▴
Rule
1 pathogenic change at same codon for Moderate; at least 2 different pathogenic changes at same codon observed in at least 5 probands for Strong
Evidence considered
- BRAF RASopathy specification allows PM5 Moderate or Strong depending same-codon evidence
Still missing
- Direct review of same-codon pathogenic missense substitutions
- Confirmed same-codon proband count if considering PM5_Strong
Sources
PM6 No assumed or confirmed de novo point total for this variant was directly established from the reviewed evidence, so PM6 was not applied. Details ▾Hide ▴
Rule
Point-based de novo scoring: 2 points strong, 1 moderate, 0.5 supporting
Evidence considered
- RASopathy specification uses a point-based assumed de novo framework
- Reviewed sources did not provide a directly verified PM6 point total for this variant
Still missing
- Case-level parental testing details
- Assumed de novo point count under the RASopathy framework
Sources
PP1 No segregation data were identified showing this variant cosegregates with disease across the number of informative meioses required for PP1. Details ▾Hide ▴
Rule
At least 3 informative meioses for Supporting, 5 for Moderate, 7 for Strong
Evidence considered
- RASopathy specification requires at least 3 informative meioses for PP1
Still missing
- Pedigree-level segregation data
- Informative meiosis count
Sources
PP2 The BRAF RASopathy specification uses a missense constraint threshold of z score greater than 3.09 for PP2, and that gene-level value was not directly available in the reviewed evidence. Details ▾Hide ▴
Rule
Missense z score >3.09 in gnomAD
Evidence considered
- PP2 rule in the BRAF RASopathy specification depends on missense z score >3.09
Still missing
- Direct gene-level missense z score for BRAF
Sources
BS2 No evidence was identified showing this variant in unaffected individuals at the point threshold required for BS2. Details ▾Hide ▴
Rule
-4 points for Strong; -1 point for Supporting
Evidence considered
- RASopathy specification uses a point-based BS2 framework
Still missing
- Unaffected carrier data with point scoring
Sources
BS4 No nonsegregation data were identified for this variant, so BS4 was not applied. Details ▾Hide ▴
Rule
Requires only one informative meiosis
Evidence considered
- RASopathy specification allows BS4 with one informative meiosis
Still missing
- Informative nonsegregation evidence
Sources
BP2 No phase or co-occurrence evidence meeting the RASopathy point-based BP2 thresholds was identified. Details ▾Hide ▴
Rule
At least -1 point Supporting, at least -2 points Moderate, at least -4 points Strong
Evidence considered
- RASopathy specification uses a point-based BP2 framework
Still missing
- Phase-confirmed co-occurrence evidence with point scoring
Sources
BP5 No alternative molecular explanation data meeting the RASopathy point-based BP5 thresholds were identified. Details ▾Hide ▴
Rule
At least -1 point Supporting, at least -2 points Moderate, at least -4 points Strong
Evidence considered
- RASopathy specification uses a point-based BP5 framework
Still missing
- Point-based evidence for an alternate cause of disease
Sources
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant, and the BRAF RASopathy specification does not apply PVS1 to this variant type. Details ▾Hide ▴
Rule
BRAF RASopathy VCEP: PVS1 not applicable
Evidence considered
- BRAF RASopathy specification marks PVS1 as not applicable
- Generic PVS1 scaffold indicates this variant is not a null-variant class
Sources
PM3 N/APM3 is not applicable in this BRAF RASopathy framework. Details ▾Hide ▴
Rule
Not applicable
Evidence considered
- BRAF RASopathy specification marks PM3 as not applicable
Sources
PM4 N/AThis is a missense variant and does not cause a protein length change, so PM4 does not apply. Details ▾Hide ▴
Rule
Protein length changes only
Evidence considered
- Protein consequence is p.Thr599Arg missense
Sources
PP4 N/APP4 is not applicable in this BRAF RASopathy framework. Details ▾Hide ▴
Rule
Not applicable
Evidence considered
- BRAF RASopathy specification marks PP4 as not applicable
Sources
BS3 N/ABS3 is not applicable in this BRAF RASopathy framework. Details ▾Hide ▴
Rule
Not applicable
Evidence considered
- BRAF RASopathy specification marks BS3 as not applicable
Sources
BP1 N/AThis is a missense variant, whereas the BRAF RASopathy specification limits BP1 to truncating loss-of-function variant types in genes without an established loss-of-function disease mechanism. Details ▾Hide ▴
Rule
Use for truncating variants in genes without established LOF correlation to disease
Evidence considered
- Variant consequence is missense p.Thr599Arg
Sources
BP3 N/ABP3 is not applicable in this BRAF RASopathy framework. Details ▾Hide ▴
Rule
Not applicable
Evidence considered
- BRAF RASopathy specification marks BP3 as not applicable
Sources
BP6 N/ABP6 is not applicable in this BRAF RASopathy framework. Details ▾Hide ▴
Rule
Not applicable
Evidence considered
- BRAF RASopathy specification marks BP6 as not applicable
Sources
BP7 N/AThis is not a synonymous, intronic, or non-coding variant, so BP7 does not apply. Details ▾Hide ▴
Rule
Synonymous or eligible non-coding variant with no predicted splice impact
Evidence considered
- Protein consequence is missense p.Thr599Arg
- SpliceAI max delta 0.00
Sources
Identifiers
- Gene
- BRAF
- Transcript
- NM_001354609.1
- Coding (HGVS c.)
- NM_001354609.1:c.1796C>G
- Protein (HGVS p.)
- NP_001341538.1:p.(Thr599Arg)
- GRCh38
- chr7:140753339 G>C
- GRCh37
- chr7:140453139 G>C
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
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 Computational evidence does not meet the BRAF RASopathy threshold for PP3. REVEL is 0.359, which is below the required threshold of 0.7, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00. BayesDel is 0.308415, but this does not change the VCEP missense rule application. Details ▾Hide ▴
Rule
For missense variants: REVEL ≥0.7; for splicing impact, predicted outcome must match disease mechanism
Evidence considered
- REVEL 0.359
- SpliceAI max delta 0.00
- BayesDel 0.308415
Sources
BP4 Computational evidence does not meet the BRAF RASopathy threshold for BP4. REVEL is 0.359, which is above the benign threshold of 0.3, although SpliceAI predicts no significant splice impact with a maximum delta score of 0.00. BayesDel is 0.308415, but the VCEP missense rule is not met. Details ▾Hide ▴
Rule
For missense variants: REVEL ≤0.3
Evidence considered
- REVEL 0.359
- SpliceAI max delta 0.00
- BayesDel 0.308415
Sources
BP7 N/AThis is not a synonymous, intronic, or non-coding variant, so BP7 does not apply. Details ▾Hide ▴
Rule
Synonymous or eligible non-coding variant with no predicted splice impact
Evidence considered
- Protein consequence is missense p.Thr599Arg
- SpliceAI max delta 0.00
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.359. BayesDel score = 0.308415.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
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/280033/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/7-140453139-G-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr7-140753339-G-C?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001354609.1%3Ac.1…
- OncoKB ↗www.oncokb.org/gene/BRAF/T599R
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=189895436
- 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
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Pathogenic (4 clinical laboratories) and as Pathogenic by ClinGen RASopathy Variant Curation Expert Panel (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.359. BayesDel score = 0.308415.
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 does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV56167356, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.