About BRAF
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRAF c.739T>C, p.(Phe247Leu)
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
PM1Moderate
PM1 · moderate
This missense variant is in BRAF exon 6, and the BRAF RASopathy specification lists exon 6 as a critical, well-established region eligible for PM1.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, which meets the BRAF RASopathy PM2 requirement of absence from population controls.
PP2Supporting
PP2 · supporting
This is a missense variant in BRAF, a gene with missense-mediated RASopathy disease, and the gene-level gnomAD missense z score is 3.72, which is above the BRAF RASopathy PP2 threshold of 3.09.
PP3Supporting
PP3 · supporting
Computational evidence supports a deleterious missense effect: REVEL is 0.902, which is above the BRAF RASopathy PP3 threshold of 0.7, while SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.10. BayesDel is also positive at 0.278133.
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: PM1 moderate, PM2 supporting, PP2 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.
SpliceAI score
0.100 maximum delta
Recorded SpliceAI maximum delta score: 0.100. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
5 reported laboratory submissions
4 Pathogenic · 1 Likely pathogenic.
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.
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 · 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.739T>C (p.Phe247Leu) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as pathogenic, including by the ClinGen RASopathy Variant Curation Expert Panel.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, consistent with the BRAF RASopathy PM2_Supporting requirement for absence from population controls.
This missense change lies in BRAF exon 6, a region specifically designated by the BRAF RASopathy specification as eligible for PM1.
Computational evidence supports a deleterious effect, with REVEL 0.902 above the BRAF RASopathy PP3 threshold of 0.7, BayesDel 0.278133, and SpliceAI showing no meaningful splice impact with a maximum delta score of 0.10.
No criteria match.
Met · 5
PM1 ModerateThis missense variant is in BRAF exon 6, and the BRAF RASopathy specification lists exon 6 as a critical, well-established region eligible for PM1. 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 localizes to exon 6
- BRAF RASopathy PM1 rule explicitly includes exon 6
Sources
PM2 SupportingThis variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, which meets the BRAF RASopathy PM2 requirement of 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
Sources
PP2 SupportingThis is a missense variant in BRAF, a gene with missense-mediated RASopathy disease, and the gene-level gnomAD missense z score is 3.72, which is above the BRAF RASopathy PP2 threshold of 3.09. Details ▾Hide ▴
Rule
Missense z score is >3.09 in gnomAD.
Evidence considered
- BRAF RASopathy PP2 threshold is missense z score >3.09
- Live gnomAD gene constraint query showed missense z score 3.72
Sources
PP3 SupportingComputational evidence supports a deleterious missense effect: REVEL is 0.902, which is above the BRAF RASopathy PP3 threshold of 0.7, while SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.10. BayesDel is also positive at 0.278133. Details ▾Hide ▴
Rule
For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.
Evidence considered
- REVEL 0.902
- SpliceAI max delta 0.10
- BayesDel 0.278133
Sources
PP5 SupportingExpert panel ClinGen RASopathy Variant Curation Expert Panel classified as Pathogenic. Details ▾Hide ▴
Not met · 3 · evaluated, threshold not reached
BA1 This variant is absent from gnomAD v2.1 and v4.1 and therefore is below the BRAF RASopathy BA1 threshold of 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 v4.1 and therefore is below the BRAF RASopathy BS1 threshold of 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
BP4 Although SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.10, the missense REVEL score is 0.902, which is well above the BRAF RASopathy BP4 threshold of 0.3, so benign computational evidence is not supported. Details ▾Hide ▴
Rule
For missense variants: REVEL ≤0.3.
Evidence considered
- REVEL 0.902
- SpliceAI max delta 0.10
Sources
Not assessed · 11 · no assessment recorded
PS1 No verified evidence was identified showing the same amino acid change from a different nucleotide substitution, or an established analogous RAF1/BRAF residue match that satisfies the BRAF RASopathy PS1 rule. 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
- BRAF RASopathy PS1 allows same amino acid change and analogous RAF1/BRAF residue use
- No confirmed qualifying comparator was recovered
Still missing
- Direct same-amino-acid comparator evidence was not identified.
- No verified analogous RAF1 comparator meeting the VCEP PS1 rule was confirmed.
Sources
cspec ↗vcep_raf_alignment
PS2 Published evidence suggesting possible de novo occurrence was flagged for follow-up, but no directly verified proband-level parental testing details were available to assign de novo points under the BRAF RASopathy framework. Details ▾Hide ▴
Rule
Follow SVI point-based de novo scoring; 4 points = Very Strong, 2 points = Strong, 1 point = Moderate.
Evidence considered
- Exploratory review identified literature that may contain de novo information
- No verified point total for PS2 was established
Still missing
- Need exact proband-level de novo wording.
- Need confirmation of both maternity and paternity
- or documentation supporting reduced PM6-style points instead.
Sources
PS3 Review of the RASopathy VCEP approved functional study materials did not confirm this exact variant in a qualifying approved assay, so pathogenic functional evidence was not applied. Details ▾Hide ▴
Rule
Two or more different approved assays = Moderate; one approved assay = Supporting.
Evidence considered
- Approved functional study summary reviewed
- OncoKB linked functional literature
- but exact variant-specific VCEP-approved assay evidence was not verified
Still missing
- Need direct evidence that p.(Phe247Leu) was tested in one or more VCEP-approved assays.
- Need exact assay result details if variant-specific functional data exist.
Sources
cspec ↗vcep_svi_rasopathy_vcep_v2_approved_functional_studiesoncokb ↗PMID:28512244 ↗PMID:29533785 ↗PMID:31515458 ↗285122442953378531515458
PS4 The variant is reported in ClinVar, but a deduplicated count of unrelated affected individuals and the corresponding RASopathy point total were not directly verified from the available materials, so PS4 was not assigned. Details ▾Hide ▴
Rule
Use RASopathy point-based PS4 scoring; 5 points = Strong, 3 points = Moderate, 1 point = Supporting.
Evidence considered
- ClinVar expert panel pathogenic assertion
- Exploratory literature review identified possible case-series sources
Still missing
- Need deduplicated unrelated affected proband count for this exact variant.
- Need direct application of the RASopathy point-based PS4 framework.
Sources
clinvar ↗cspec ↗PMID:20301303 ↗PMID:20301365 ↗PMID:20876176 ↗PMID:25173338 ↗20301303203013652087617625173338
PM5 The BRAF framework uses classic same-residue PM5 logic, but no verified qualifying pathogenic or likely pathogenic missense comparator at codon 247 was confirmed from the available materials. Details ▾Hide ▴
Rule
Strong: ≥2 different [likely] pathogenic residue changes at the same codon observed in ≥5 probands. Moderate: 1 [likely] pathogenic residue change at the same codon.
Evidence considered
- PM5 uses same-residue missense logic in the BRAF framework
- No confirmed qualifying comparator was available
Still missing
- Need confirmed same-codon pathogenic or likely pathogenic comparator evidence.
- The harvested PM5 candidate artifact did not provide a usable comparator determination for this case.
Sources
cspec ↗pm5_candidates
PM6 Possible de novo literature sources were identified, but no directly verified report was available to determine whether reduced de novo points should be assigned under PM6. Details ▾Hide ▴
Rule
2 points = Strong, 1 point = Moderate, 0.5 points = Supporting.
Evidence considered
- Potential inheritance sources identified
- No verified PM6 point total established
Still missing
- Need exact inheritance wording for reported probands.
- Need to determine whether any event is assumed de novo rather than fully confirmed.
Sources
PP1 No segregation data were identified showing this variant co-segregating with disease in informative meioses. Details ▾Hide ▴
Rule
Strong: ≥7 informative meioses. Moderate: ≥5. Supporting: ≥3.
Evidence considered
- No informative segregation evidence was verified
Still missing
- Need family-based segregation data with informative meiosis counts.
Sources
BS2 No evidence was identified showing this variant in unaffected individuals sufficient to assign benign observation points. Details ▾Hide ▴
Rule
-4 points = Strong; -1 point = Supporting.
Evidence considered
- No unaffected carrier data were verified
Still missing
- Need confirmed unaffected carrier observations meeting the RASopathy point framework.
Sources
BS4 No lack-of-segregation evidence was identified for this variant in an informative family. Details ▾Hide ▴
Rule
Requires only one informative meiosis.
Evidence considered
- No informative non-segregation evidence was verified
Still missing
- Need family data showing the variant does not segregate with disease.
Sources
BP2 No co-occurrence or phase data were identified showing this variant with an alternative molecular cause of disease in the same gene. Details ▾Hide ▴
Rule
Strong: ≥(-4) points. Moderate: ≥(-2) points. Supporting: ≥(-1) point.
Evidence considered
- No confirmed qualifying co-occurrence observation was available
Still missing
- Need explicit co-occurrence data and phase information.
Sources
BP5 No alternative molecular explanation for the phenotype was identified that would support benign points under BP5. Details ▾Hide ▴
Rule
Strong: ≥(-4) points. Moderate: ≥(-2) points. Supporting: ≥(-1) point.
Evidence considered
- No qualifying alternate cause evidence was verified
Still missing
- Need verified alternate molecular diagnosis information if present.
Sources
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 VCEPThis is a missense variant, not a predicted null variant, and the BRAF RASopathy framework marks PVS1 as not applicable for this case. Details ▾Hide ▴
VCEP rule
PVS1 not applicable for this VCEP case.
Evidence considered
- Missense change p.(Phe247Leu)
- PVS1 marked not applicable in the BRAF RASopathy framework
Sources
PM3 VCEPPM3 is not used in the BRAF RASopathy framework for this autosomal dominant disorder context. Details ▾Hide ▴
VCEP rule
Not applicable.
Evidence considered
- PM3 marked not applicable in BRAF criteria
Sources
PM4 N/AThis is a missense substitution and does not cause a protein length change, so PM4 does not apply. Details ▾Hide ▴
Rule
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
Evidence considered
- Variant is missense
- not in-frame indel or stop-loss
Sources
PP4 VCEPPP4 is not used in the BRAF RASopathy framework because phenotype-based case evidence is incorporated through PS4. Details ▾Hide ▴
VCEP rule
Not applicable, see PS4.
Evidence considered
- PP4 marked not applicable in BRAF criteria
Sources
BS3 VCEPBS3 is not applicable in the BRAF RASopathy framework for this case. Details ▾Hide ▴
VCEP rule
Not applicable.
Evidence considered
- BS3 marked not applicable in BRAF criteria
Sources
BP1 N/ABP1 in the BRAF RASopathy framework is reserved for truncating loss-of-function variants in a gain-of-function disease setting, and this variant is missense. Details ▾Hide ▴
Rule
Use for truncating variants in genes without established LOF correlation to disease in the RASopathy gain-of-function setting.
Evidence considered
- Variant is missense
- BRAF BP1 is for truncating variants in this framework
Sources
BP3 VCEPBP3 is not applicable in the BRAF RASopathy framework. Details ▾Hide ▴
VCEP rule
Not applicable.
Evidence considered
- BP3 marked not applicable in BRAF criteria
Sources
BP6 VCEPBP6 is not used in this VCEP framework, so outside benign assertions were not counted as independent evidence. Details ▾Hide ▴
VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
- BP6 marked not applicable in BRAF criteria
Sources
BP7 N/AThis is not a synonymous, intronic, or other non-coding variant, so BP7 does not apply. Details ▾Hide ▴
Rule
Applicable to synonymous, intronic non-canonical splice, or non-coding variants with no predicted splice impact and low conservation.
Evidence considered
- Missense variant p.(Phe247Leu)
Sources
Identifiers
- Gene
- BRAF
- Transcript
- NM_001354609.1
- Coding (HGVS c.)
- NM_001354609.1:c.739T>C
- Protein (HGVS p.)
- NP_001341538.1:p.(Phe247Leu)
- GRCh38
- chr7:140801533 A>G
- GRCh37
- chr7:140501333 A>G
- ClinVar
- 180784
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.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.902
- BayesDel
- 0.278
How the predictions were used
PP3 SupportingComputational evidence supports a deleterious missense effect: REVEL is 0.902, which is above the BRAF RASopathy PP3 threshold of 0.7, while SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.10. BayesDel is also positive at 0.278133. Details ▾Hide ▴
Rule
For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.
Evidence considered
- REVEL 0.902
- SpliceAI max delta 0.10
- BayesDel 0.278133
Sources
BP4 Although SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.10, the missense REVEL score is 0.902, which is well above the BRAF RASopathy BP4 threshold of 0.3, so benign computational evidence is not supported. Details ▾Hide ▴
Rule
For missense variants: REVEL ≤0.3.
Evidence considered
- REVEL 0.902
- SpliceAI max delta 0.10
Sources
BP7 N/AThis is not a synonymous, intronic, or other non-coding variant, so BP7 does not apply. Details ▾Hide ▴
Rule
Applicable to synonymous, intronic non-canonical splice, or non-coding variants with no predicted splice impact and low conservation.
Evidence considered
- Missense variant p.(Phe247Leu)
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10). REVEL score = 0.902. BayesDel score = 0.278133.
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
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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.
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PMID 29533785 ↗Systematic Functional Annotation of Somatic Mutations in Cancer.No paper-specific finding is recorded.
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PMID 31515458 ↗Response to Anti-EGFR Therapy in Patients with BRAF non-V600-Mutant Metastatic Colorectal Cancer.No paper-specific finding is recorded.
-
PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.No paper-specific finding is recorded.
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PMID 20301303 ↗Noonan Syndrome.Adam MP et al. · 1993No paper-specific finding is recorded.
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PMID 20301365 ↗PMID:20301365No paper-specific finding is recorded.
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PMID 20876176 ↗Noonan syndrome: clinical features, diagnosis, and management guidelines.Romano AA et al. · 2010No paper-specific finding is recorded.
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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.
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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
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.100
Open source ↗
ClinVar
4 Pathogenic · 1 Likely 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/180784/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/7-140501333-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr7-140801533-A-G?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001354609.1%3Ac.7…
- OncoKB ↗www.oncokb.org/gene/BRAF/F247L
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRAF+c.739T%3EC
- 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 Likely pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen RASopathy Variant Curation Expert Panel (expert panel). (ClinVarID = 180784)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10). REVEL score = 0.902. BayesDel score = 0.278133.
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 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.