About BRAF
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRAF c.1787G>T, p.(Gly596Val)
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
PS3Supporting
PS3 · supporting
In a published functional study, expression of BRAF p.(Gly596Val) in zebrafish caused abnormal embryonic elongation and developmental abnormalities, and phospho-ERK assays showed downstream ERK activation, consistent with dysregulated MAPK signaling. These data support an abnormal functional effect consistent with the disease mechanism and support PS3 at Supporting strength.
PM1Moderate
PM1 · moderate
This missense variant affects Gly596, which lies within the BRAF CR3 activation segment (amino acids 594-627), a critical and well-established functional domain specifically listed for PM1 in the BRAF RASopathy specification. This meets PM1 at Moderate strength.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1. Under the BRAF RASopathy specification, absence from gnomAD meets PM2 at Supporting strength.
PP3Supporting
PP3 · supporting
Computational evidence supports a deleterious missense effect. REVEL is 0.989, which is above the BRAF RASopathy PP3 threshold of 0.7, BayesDel is 0.588239, and SpliceAI predicts no significant splice impact with a maximal delta score of 0.07. For this missense variant, the available computational evidence supports PP3 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 supporting, 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
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.
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: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
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 · 5 not met · 9 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.1787G>T (p.Gly596Val) variant has been observed in somatic cancers in COSMIC and has been reported in ClinVar as Pathogenic with expert-panel review.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports rarity in population reference datasets.
In a published functional study, BRAF p.Gly596Val caused abnormal zebrafish developmental phenotypes and showed downstream ERK activation, consistent with dysregulated MAPK signaling.
Computational evidence supports a deleterious missense effect, with REVEL 0.989 above the BRAF PP3 threshold of 0.7, BayesDel 0.588239, and SpliceAI predicting no significant splice effect with a maximal delta score of 0.07.
No criteria match.
Met · 5
PS3 SupportingIn a published functional study, expression of BRAF p.(Gly596Val) in zebrafish caused abnormal embryonic elongation and developmental abnormalities, and phospho-ERK assays showed downstream ERK activation, consistent with dysregulated MAPK signaling. These data support an abnormal functional effect consistent with the disease mechanism and support PS3 at Supporting strength. Details ▾Hide ▴
Rule
BRAF RASopathy PS3: Supporting for one approved assay; Moderate for two or more different approved assays.
Evidence considered
- Zebrafish developmental assay for BRAF G596V
- Phospho-ERK functional readout
- RASopathy VCEP approved functional studies resource
Still missing
- Direct review of the full approved-assay evidence package could further confirm whether additional approved assays justify a higher strength.
Sources
PM1 ModerateThis missense variant affects Gly596, which lies within the BRAF CR3 activation segment (amino acids 594-627), a critical and well-established functional domain specifically listed for PM1 in the BRAF RASopathy specification. This meets PM1 at Moderate strength. Details ▾Hide ▴
Rule
PM1 applies to exon 6, exon 11, P-loop (AA 459-474), and CR3 activation segment (AA 594-627).
Evidence considered
- Variant protein consequence p.(Gly596Val)
- BRAF CR3 activation segment 594-627 listed in CSPEC
Sources
PM2 SupportingThis variant is absent from gnomAD v2.1 and absent from gnomAD v4.1. Under the BRAF RASopathy specification, absence from gnomAD meets PM2 at Supporting strength. Details ▾Hide ▴
Rule
PM2 Supporting: variant must be absent from controls (gnomAD).
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
Sources
PP3 SupportingComputational evidence supports a deleterious missense effect. REVEL is 0.989, which is above the BRAF RASopathy PP3 threshold of 0.7, BayesDel is 0.588239, and SpliceAI predicts no significant splice impact with a maximal delta score of 0.07. For this missense variant, the available computational evidence supports PP3 at Supporting strength. Details ▾Hide ▴
Rule
PP3 Supporting for missense variants when REVEL is at least 0.7; predicted splicing impact must match disease mechanism when relevant.
Evidence considered
- REVEL 0.989
- BayesDel 0.588239
- SpliceAI max delta 0.07
Sources
Not met · 5 · evaluated, threshold not reached
PS1 No different nucleotide change producing the same amino acid substitution, p.(Gly596Val), was identified from the reviewed evidence, so PS1 is not met. Details ▾Hide ▴
Rule
PS1 requires the same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Evidence considered
- ClinVar record for p.(Gly596Val)
- BRAF CSPEC PS1 rule
Still missing
- A broader same-amino-acid search across external variant databases could be performed if needed.
Sources
PM5 A different missense change at the same codon, p.(Gly596Cys), was identified in ClinVar, but it has conflicting classifications of pathogenicity rather than an established pathogenic or likely pathogenic classification. Therefore the BRAF same-codon PM5 rule is not met from the reviewed evidence. Details ▾Hide ▴
Rule
PM5 Moderate requires one pathogenic or likely pathogenic residue change at the same codon; PM5 Strong requires at least two such changes observed in at least five probands.
Evidence considered
- Same-codon ClinVar search identified p.(Gly596Cys) with conflicting classification
- BRAF CSPEC PM5 rule
Still missing
- Confirmation of an established pathogenic or likely pathogenic alternate missense change at codon 596 in BRAF or the analogous RAF1 residue
- if present
Sources
BA1 This variant is absent from gnomAD and does not reach the BRAF RASopathy BA1 threshold of at least 0.05% filtering allele frequency. Details ▾Hide ▴
Rule
BA1 requires gnomAD filtering allele frequency at least 0.05%.
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
Sources
BS1 This variant is absent from gnomAD and does not reach the BRAF RASopathy BS1 threshold of at least 0.025% filtering allele frequency. Details ▾Hide ▴
Rule
BS1 requires gnomAD filtering allele frequency at least 0.025%.
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
Sources
BP4 Available computational evidence does not support a benign effect. REVEL is 0.989, which is above the benign BP4 threshold of 0.3, and BayesDel is positive at 0.588239. SpliceAI predicts no significant splice impact with a maximal delta score of 0.07, but this does not overcome the strongly deleterious missense prediction profile. Details ▾Hide ▴
Rule
BP4 Supporting for missense variants requires REVEL at most 0.3.
Evidence considered
- REVEL 0.989
- BayesDel 0.588239
- SpliceAI max delta 0.07
Sources
Not assessed · 9 · no assessment recorded
PS2 Published disease association is strong, but no directly reviewed case-level evidence in the available materials confirmed a de novo occurrence with sufficient parentage documentation to score PS2 points. Details ▾Hide ▴
Rule
PS2 is point based in the BRAF RASopathy specification.
Evidence considered
- BRAF CSPEC PS2 point-based rule
- ClinVar expert-panel record
- RASopathy literature indicates de novo disease mechanism at the gene level
Still missing
- Case-level inheritance data with maternity and paternity assessment
- Point-based PS2 documentation under the RASopathy framework
Sources
PS4 This variant has been reported in ClinVar and has been observed in somatic cancer databases, but the available materials do not provide the unrelated germline proband counts or point-based case evidence needed to apply the BRAF RASopathy PS4 rule. Details ▾Hide ▴
Rule
PS4 is point based in the BRAF RASopathy specification.
Evidence considered
- ClinVar pathogenic expert-panel record
- OncoKB literature gateway
- BRAF CSPEC PS4 point-based rule
Still missing
- Unrelated affected proband counts
- Point-based PS4 scoring evidence under the RASopathy specification
Sources
PM6 No directly reviewed case-level evidence showed this variant as assumed de novo with the documentation needed to assign PM6 points. Details ▾Hide ▴
Rule
PM6 is point based in the BRAF RASopathy specification.
Evidence considered
- BRAF CSPEC PM6 point-based rule
- ClinVar pathogenic record without case-level point assignment
Still missing
- Case-level inheritance wording for exact variant occurrences
- Point-based PM6 scoring evidence
Sources
PP1 No segregation data were identified for this variant, so PP1 cannot be applied. Details ▾Hide ▴
Rule
PP1 Supporting requires at least 3 informative meioses in the BRAF RASopathy specification.
Evidence considered
- No segregation evidence in the reviewed materials
Still missing
- Informative meioses demonstrating co-segregation with phenotype
Sources
PP2 The BRAF RASopathy specification allows PP2 when the missense constraint z score is greater than 3.09, but no directly reviewed gene-level missense z score was identified in the available materials for this adjudication. Details ▾Hide ▴
Rule
PP2 Supporting: missense z score greater than 3.09 in gnomAD.
Evidence considered
- BRAF CSPEC PP2 rule
Still missing
- Gene-level missense constraint z score confirmation
Sources
BS2 No evidence was identified showing this variant in unaffected individuals in a quantity sufficient to assign BS2 points. Details ▾Hide ▴
Rule
BS2 is point based in the BRAF RASopathy specification.
Evidence considered
- No unaffected-carrier evidence in the reviewed materials
Still missing
- Documented unaffected carriers with point-based BS2 scoring
Sources
BS4 No non-segregation evidence was identified for this variant, so BS4 cannot be applied. Details ▾Hide ▴
Rule
BS4 requires one informative meiosis in the BRAF RASopathy specification.
Evidence considered
- No family non-segregation evidence in the reviewed materials
Still missing
- Informative non-segregation data in at least one meiosis
Sources
BP2 No phase data or point-based evidence were identified to support BP2. Details ▾Hide ▴
Rule
BP2 is point based in the BRAF RASopathy specification.
Evidence considered
- No phase evidence in the reviewed materials
Still missing
- Confirmed in-trans or in-cis observations with scoring details
Sources
BP5 No evidence was identified for an alternate molecular explanation with point-based support to apply BP5. Details ▾Hide ▴
Rule
BP5 is point based in the BRAF RASopathy specification.
Evidence considered
- No alternate-cause evidence in the reviewed materials
Still missing
- Documented alternate cause with BP5 point assignment
Sources
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant, not a null variant, and the BRAF RASopathy specification lists PVS1 as not applicable for this variant type. Details ▾Hide ▴
Rule
PVS1 not applicable in the BRAF RASopathy specification for this missense variant.
Evidence considered
- Missense change p.(Gly596Val)
- BRAF CSPEC marks PVS1 not applicable
Sources
PM3 N/APM3 is not applicable under the BRAF RASopathy specification. Details ▾Hide ▴
PM4 N/AThis is a missense substitution without a protein length change, so PM4 is not applicable. Details ▾Hide ▴
Rule
PM4 applies to protein length changes, not a simple missense substitution.
Evidence considered
- Missense variant p.(Gly596Val)
Sources
PP4 N/APP4 is not applicable under the BRAF RASopathy specification. Details ▾Hide ▴
BS3 N/ABS3 is not applicable under the BRAF RASopathy specification. Details ▾Hide ▴
BP1 N/AThis is not a truncating variant, so the BRAF RASopathy BP1 truncating-variant rule is not applicable. Details ▾Hide ▴
Rule
BP1 in the BRAF RASopathy specification applies to truncating variants in this gain-of-function disease context.
Evidence considered
- Missense variant p.(Gly596Val)
Sources
BP3 N/ABP3 is not applicable under the BRAF RASopathy specification. Details ▾Hide ▴
BP6 N/ABP6 is not applicable under the BRAF RASopathy specification. Details ▾Hide ▴
BP7 N/AThis is a missense variant rather than a synonymous or eligible intronic variant, so BP7 is not applicable. Details ▾Hide ▴
Rule
BP7 applies to synonymous or eligible intronic/non-coding variants with no predicted splice impact.
Evidence considered
- Missense variant p.(Gly596Val)
Sources
Identifiers
- Gene
- BRAF
- Transcript
- NM_001354609.1
- Coding (HGVS c.)
- NM_001354609.1:c.1787G>T
- Protein (HGVS p.)
- NP_001341538.1:p.(Gly596Val)
- GRCh38
- chr7:140753348 C>A
- GRCh37
- chr7:140453148 C>A
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 SupportingComputational evidence supports a deleterious missense effect. REVEL is 0.989, which is above the BRAF RASopathy PP3 threshold of 0.7, BayesDel is 0.588239, and SpliceAI predicts no significant splice impact with a maximal delta score of 0.07. For this missense variant, the available computational evidence supports PP3 at Supporting strength. Details ▾Hide ▴
Rule
PP3 Supporting for missense variants when REVEL is at least 0.7; predicted splicing impact must match disease mechanism when relevant.
Evidence considered
- REVEL 0.989
- BayesDel 0.588239
- SpliceAI max delta 0.07
Sources
BP4 Available computational evidence does not support a benign effect. REVEL is 0.989, which is above the benign BP4 threshold of 0.3, and BayesDel is positive at 0.588239. SpliceAI predicts no significant splice impact with a maximal delta score of 0.07, but this does not overcome the strongly deleterious missense prediction profile. Details ▾Hide ▴
Rule
BP4 Supporting for missense variants requires REVEL at most 0.3.
Evidence considered
- REVEL 0.989
- BayesDel 0.588239
- SpliceAI max delta 0.07
Sources
BP7 N/AThis is a missense variant rather than a synonymous or eligible intronic variant, so BP7 is not applicable. Details ▾Hide ▴
Rule
BP7 applies to synonymous or eligible intronic/non-coding variants with no predicted splice impact.
Evidence considered
- Missense variant p.(Gly596Val)
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07). REVEL score = 0.989. BayesDel score = 0.588239.
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/40387/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/7-140453148-C-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr7-140753348-C-A?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001354609.1%3Ac.1…
- OncoKB ↗www.oncokb.org/gene/BRAF/G596V
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=189919256
- 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 (10 clinical laboratories) and as Likely pathogenic (1 clinical laboratory) 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 = 0.07). REVEL score = 0.989. BayesDel score = 0.588239.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV99951808, n = 1 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.