About BRAF
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRAF c.739T>G, p.(Phe247Val)
Classification
Likely pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic classification under the recorded framework.
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
PM1Moderate
PM1 · moderate
This missense variant lies in BRAF exon 6, which is one of the gene regions explicitly designated by the RASopathy VCEP as eligible for PM1 application.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, which meets the BRAF RASopathy VCEP PM2 threshold requiring absence from population controls.
PM5Moderate
PM5 · moderate
Other pathogenic or likely pathogenic missense changes have been reported at the same BRAF codon 247 in ClinVar, including p.(Phe247Leu) and p.(Phe247Ser), which supports PM5 at moderate strength under the RASopathy VCEP rule for one pathogenic or likely pathogenic residue change at the same codon.
PP3Supporting
PP3 · supporting
Computational evidence supports a deleterious missense effect: REVEL is 0.921, which is above the RASopathy VCEP PP3 threshold of 0.7, and BayesDel is also positive at 0.434669. SpliceAI shows only a possible splice signal with max delta score 0.20, so PP3 is supported primarily by the missense prediction evidence.
PP5Supporting
PP5 · supporting
Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Likely pathogenic.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
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: PM1 moderate, PM2 supporting, PM5 moderate, PP3 supporting, PP5 supporting; maps to Likely Pathogenic.
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.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.200 maximum delta
Recorded SpliceAI maximum delta score: 0.200. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
5 reported laboratory submissions
2 Pathogenic · 2 Likely pathogenic · 1 Uncertain significance.
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BRAF, an intracellular kinase, is frequently mutated in melanoma, thyroid and lung cancers among others.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
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: 5 met · 5 not met · 10 not assessed · 8 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.739T>G (p.Phe247Val) variant has not been observed in COSMIC and has been reported in ClinVar, where the overall classification is likely pathogenic with expert panel review.
This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, which supports PM2 at supporting strength under the BRAF RASopathy specification.
This missense variant lies in BRAF exon 6, a region explicitly designated by the RASopathy VCEP for PM1 application, and other pathogenic or likely pathogenic missense changes have been reported at the same codon 247, supporting PM5 at moderate strength.
Computational evidence supports a deleterious missense effect because REVEL is 0.921, above the VCEP PP3 threshold of 0.7, BayesDel is positive at 0.434669, and SpliceAI shows only a possible splice signal with a max delta score of 0.20.
No criteria match.
Met · 5
PM1 ModerateThis missense variant lies in BRAF exon 6, which is one of the gene regions explicitly designated by the RASopathy VCEP as eligible for PM1 application. Details ▾Hide ▴
Rule
Applicable only to critical and well-established functional domains available in the supplementary table (exon 6, exon 11, P-loop [AA 459-474], CR3 activation segment [AA 594-627]).
Evidence considered
- Variant maps to exon 6
- BRAF RASopathy VCEP PM1 regional rule
Sources
PM2 SupportingThis variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, which meets the BRAF RASopathy VCEP PM2 threshold requiring absence from population controls. Details ▾Hide ▴
Rule
The variant must be absent from controls (gnomAD).
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
- Absent from gnomAD-Canada
Sources
PM5 ModerateOther pathogenic or likely pathogenic missense changes have been reported at the same BRAF codon 247 in ClinVar, including p.(Phe247Leu) and p.(Phe247Ser), which supports PM5 at moderate strength under the RASopathy VCEP rule for one pathogenic or likely pathogenic residue change at the same codon. Details ▾Hide ▴
Rule
Moderate: 1 pathogenic/likely pathogenic residue change at the same codon; Strong: at least 2 different pathogenic/likely pathogenic residue changes at the same codon observed in at least 5 probands.
Evidence considered
- ClinVar expert panel records at codon 247 include pathogenic/likely pathogenic alternate missense changes
- BRAF RASopathy VCEP PM5 same-codon rule
Still missing
- A full codon-level curation would be needed to determine whether PM5_Strong is justified by proband counts.
Sources
PP3 SupportingComputational evidence supports a deleterious missense effect: REVEL is 0.921, which is above the RASopathy VCEP PP3 threshold of 0.7, and BayesDel is also positive at 0.434669. SpliceAI shows only a possible splice signal with max delta score 0.20, so PP3 is supported primarily by the missense prediction evidence. Details ▾Hide ▴
Rule
For missense variants: REVEL >= 0.7. For splicing impact, predicted outcome must match disease mechanism.
Evidence considered
- REVEL 0.921
- BayesDel 0.434669
- SpliceAI max delta 0.20
Sources
PP5 SupportingExpert panel ClinGen RASopathy Variant Curation Expert Panel classified as Likely pathogenic. Details ▾Hide ▴
Not met · 5 · evaluated, threshold not reached
PS1 No evidence was identified that this nucleotide change produces the same amino acid change as a previously established pathogenic variant. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in BRAF and RAF1.
Evidence considered
- ClinVar exact variant review
- BRAF RASopathy VCEP PS1 rule
Still missing
- A dedicated search for an alternate nucleotide change causing p.(Phe247Val) could further confirm absence of PS1 evidence.
Sources
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so it is well below the BA1 threshold of at least 0.05% filtering allele frequency. Details ▾Hide ▴
Rule
GnomAD filtering allele frequency >=0.05%.
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
Sources
BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so it does not meet the BS1 threshold of at least 0.025% filtering allele frequency. Details ▾Hide ▴
Rule
GnomAD filtering allele frequency >=0.025%.
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
Sources
BP1 This criterion is reserved in the RASopathy BRAF framework for truncating loss-of-function variants in the appropriate context, whereas this variant is missense. Details ▾Hide ▴
Rule
Use for truncating variants in genes without established loss-of-function correlation to disease in the RASopathy framework.
Evidence considered
- Missense variant class
- BRAF RASopathy VCEP BP1 rule
Sources
BP4 Computational evidence does not support a benign effect because REVEL is 0.921, which is above the BP4 benign threshold of 0.3. Details ▾Hide ▴
Not assessed · 10 · no assessment recorded
PS2 Possible de novo evidence was suggested in submitted records, but no independently verified report with confirmed maternity and paternity and phenotype-specific point scoring was identified here. Details ▾Hide ▴
Rule
Point-based de novo criterion under the RASopathy VCEP framework.
Evidence considered
- ClinVar submission audit
- BRAF RASopathy VCEP PS2 point system
Still missing
- Need primary case report(s) with parental testing details
- Need point-based de novo scoring under the RASopathy VCEP framework
Sources
PS3 No approved variant-specific functional assay result for p.(Phe247Val) was identified from the reviewed materials. Available literature leads and OncoKB citations did not provide sufficient direct evidence to apply PS3. Details ▾Hide ▴
Rule
Moderate for two or more different approved assays; Supporting for one approved assay.
Evidence considered
- OncoKB showed no variant-specific reviewed functional evidence
- RASopathy VCEP approved functional studies summary reviewed
Still missing
- Need direct review of any variant-specific approved assay
- Need confirmation whether this exact variant was tested in a VCEP-approved assay and the direction of effect
Sources
oncokb ↗vcep_svi_rasopathy_vcep_v2_approved_functional_studiescspec ↗PMID:28512244 ↗PMID:29533785 ↗PMID:31515458 ↗PMID:31785789 ↗
PS4 This variant has been reported in ClinVar, but no deduplicated count of unrelated affected probands or VCEP point total was established from the reviewed evidence, so PS4 could not be applied. Details ▾Hide ▴
Rule
Point-based prevalence/case evidence under the RASopathy VCEP framework.
Evidence considered
- ClinVar expert panel presence
- BRAF RASopathy VCEP PS4 point system
Still missing
- Need deduplicated affected proband count
- Need VCEP point-based PS4 scoring
Sources
PM6 Possible de novo evidence was suggested, but the reviewed evidence did not establish the level of parental confirmation or independence needed to score PM6. Details ▾Hide ▴
Rule
Point-based de novo evidence without full confirmation under the RASopathy VCEP framework.
Evidence considered
- ClinVar submission audit
- BRAF RASopathy VCEP PM6 point system
Still missing
- Need primary report(s) clarifying whether de novo status lacked full parentage confirmation
- Need VCEP point assignment
Sources
PP1 No segregation data were identified that would allow informative meiosis counting for PP1. Details ▾Hide ▴
Rule
Supporting at at least 3 informative meioses; Moderate at at least 5; Strong at at least 7.
Evidence considered
- Reviewed ClinVar-linked evidence leads did not provide segregation counts
Still missing
- Need family-based segregation data with informative meiosis counts
Sources
PP2 The BRAF RASopathy VCEP allows PP2 for missense variants when the gnomAD missense z score is greater than 3.09, but that gene-level missense constraint value was not retrieved in the reviewed materials. Details ▾Hide ▴
Rule
Missense z score is >3.09 in gnomAD.
Evidence considered
- BRAF RASopathy VCEP PP2 rule
Still missing
- Need BRAF gnomAD missense z score
Sources
BS2 No evidence was identified showing this variant in unaffected individuals at a level that would satisfy the RASopathy VCEP point-based BS2 rule. Details ▾Hide ▴
Rule
Strong at -4 points; Supporting at -1 point.
Evidence considered
- BRAF RASopathy VCEP BS2 point system
Still missing
- Need unaffected carrier data with VCEP point scoring
Sources
BS4 No non-segregation data were identified for this variant, so BS4 could not be evaluated. Details ▾Hide ▴
Rule
Requires only one informative meiosis.
Evidence considered
- BRAF RASopathy VCEP BS4 rule
Still missing
- Need informative family data showing lack of segregation
Sources
BP2 No evidence was identified for an alternative molecular explanation or phase information that would allow BP2 point scoring. Details ▾Hide ▴
Rule
Strong at at least -4 points; Moderate at at least -2 points; Supporting at at least -1 point.
Evidence considered
- BRAF RASopathy VCEP BP2 point system
Still missing
- Need phase data and alternate molecular cause evidence if present
Sources
BP5 No evidence was identified for an alternate molecular cause sufficient to assign BP5 points. Details ▾Hide ▴
Rule
Strong at at least -4 points; Moderate at at least -2 points; Supporting at at least -1 point.
Evidence considered
- BRAF RASopathy VCEP BP5 point system
Still missing
- Need alternate molecular diagnosis evidence with VCEP point scoring
Sources
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 VCEPThis is a missense variant, and the BRAF RASopathy specification marks PVS1 as not applicable for this case. Details ▾Hide ▴
VCEP rule
Not applicable for this VCEP/case context.
Evidence considered
- BRAF RASopathy VCEP marks PVS1 not applicable
- Generic PVS1 scaffold does not place this variant in a null-variant bucket
Sources
cspec ↗pvs1_variant_assessment
PM3 VCEPPM3 is not applicable in this BRAF RASopathy framework. Details ▾Hide ▴
VCEP rule
Not applicable for this VCEP.
Evidence considered
- BRAF RASopathy VCEP PM3 applicability
Sources
PM4 N/AThis is a missense substitution and does not change protein length, so PM4 is not applicable. Details ▾Hide ▴
PP4 VCEPPP4 is not applicable in this BRAF RASopathy framework. Details ▾Hide ▴
VCEP rule
Not applicable for this VCEP.
Evidence considered
- BRAF RASopathy VCEP PP4 applicability
Sources
BS3 VCEPBS3 is not applicable in this BRAF RASopathy framework. Details ▾Hide ▴
VCEP rule
Not applicable for this VCEP.
Evidence considered
- BRAF RASopathy VCEP BS3 applicability
Sources
BP3 VCEPBP3 is not applicable in this BRAF RASopathy framework. Details ▾Hide ▴
VCEP rule
Not applicable for this VCEP.
Evidence considered
- BRAF RASopathy VCEP BP3 applicability
Sources
BP6 VCEPBP6 is not used in this VCEP framework. Details ▾Hide ▴
VCEP rule
Not applicable for this VCEP.
Evidence considered
- BRAF RASopathy VCEP BP6 applicability
Sources
BP7 N/AThis is not a synonymous, intronic, or other non-coding variant, so BP7 is not applicable. Details ▾Hide ▴
Rule
Synonymous or eligible intronic/non-coding variant with no predicted splice impact and low conservation.
Evidence considered
- Missense variant class
Sources
Identifiers
- Gene
- BRAF
- Transcript
- NM_001354609.1
- Coding (HGVS c.)
- NM_001354609.1:c.739T>G
- Protein (HGVS p.)
- NP_001341538.1:p.(Phe247Val)
- GRCh38
- chr7:140801533 A>C
- GRCh37
- chr7:140501333 A>C
- ClinVar
- 44830
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
—
Transcript span
—
Strand
—
Variants mapped
—
Source
UCSC ncbiRefSeqCurated
All variants in BRAF
—
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
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.921
- BayesDel
- 0.435
How the predictions were used
PP3 SupportingComputational evidence supports a deleterious missense effect: REVEL is 0.921, which is above the RASopathy VCEP PP3 threshold of 0.7, and BayesDel is also positive at 0.434669. SpliceAI shows only a possible splice signal with max delta score 0.20, so PP3 is supported primarily by the missense prediction evidence. Details ▾Hide ▴
Rule
For missense variants: REVEL >= 0.7. For splicing impact, predicted outcome must match disease mechanism.
Evidence considered
- REVEL 0.921
- BayesDel 0.434669
- SpliceAI max delta 0.20
Sources
BP4 Computational evidence does not support a benign effect because REVEL is 0.921, which is above the BP4 benign threshold of 0.3. Details ▾Hide ▴
BP7 N/AThis is not a synonymous, intronic, or other non-coding variant, so BP7 is not applicable. Details ▾Hide ▴
Rule
Synonymous or eligible intronic/non-coding variant with no predicted splice impact and low conservation.
Evidence considered
- Missense variant class
Sources
Statement
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.20). REVEL score = 0.921. BayesDel score = 0.434669.
9 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
-
PMID 28512244 ↗Engineering and Functional Characterization of Fusion Genes Identifies Novel Oncogenic Drivers of Cancer.Lu H et al. · 2017No paper-specific finding is recorded.
-
PMID 29533785 ↗Systematic Functional Annotation of Somatic Mutations in Cancer.No paper-specific finding is recorded.
-
PMID 31515458 ↗Response to Anti-EGFR Therapy in Patients with BRAF non-V600-Mutant Metastatic Colorectal Cancer.No paper-specific finding is recorded.
-
PMID 24033266 ↗A systematic approach to assessing the clinical significance of genetic variants.Duzkale H et al. · 2013No paper-specific finding is recorded.
-
PMID 31785789 ↗Sex-Based Analysis of De Novo Variants in Neurodevelopmental Disorders.Turner TN et al. · 2019No paper-specific finding is recorded.
-
PMID 20301303 ↗Noonan Syndrome.Adam MP et al. · 1993No paper-specific finding is recorded.
-
PMID 20301365 ↗Cardiofaciocutaneous Syndrome.Adam MP et al. · 1993No paper-specific finding is recorded.
-
PMID 25173338 ↗2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC).Authors/Task Force members et al. · 2014No paper-specific finding is recorded.
-
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
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.200
Open source ↗
ClinVar
2 Pathogenic · 2 Likely pathogenic · 1 Uncertain significance
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/44830/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/7-140501333-A-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr7-140801533-A-C?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/7-140801533-A-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001354609.1%3Ac.7…
- OncoKB ↗www.oncokb.org/gene/BRAF/F247V
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRAF+c.739T%3EG
- 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.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Pathogenic (2 clinical laboratories) and as Likely pathogenic (2 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as Likely pathogenic by ClinGen RASopathy Variant Curation Expert Panel (expert panel). (ClinVarID = 44830)
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.20). REVEL score = 0.921. BayesDel score = 0.434669.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BRAF, an intracellular kinase, is frequently mutated in melanoma, thyroid and lung cancers among others.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.