About BRAF
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRAF c.741T>G, p.(Phe247Leu)
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 is located in BRAF exon 6, and the BRAF RASopathy specification lists exon 6 as a critical and well-established functional domain for PM1 application.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, which meets the BRAF RASopathy PM2 threshold of absence from controls.
PM5Moderate
PM5 · moderate
Other missense changes at the same codon have been reported in ClinVar with expert-panel review, including p.(Phe247Val) and p.(Phe247Ser), both classified as likely pathogenic. This supports PM5 at moderate strength for a different missense change at the same residue.
PP3Supporting
PP3 · supporting
Computational evidence supports a deleterious missense effect. REVEL is 0.816, which is above the BRAF RASopathy PP3 threshold of 0.7, while SpliceAI predicts no significant splice impact with a maximum delta score of 0.08, supporting a protein-level rather than splice-driven effect.
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: 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.
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.
No listed criterion applied
OncoKB ↗
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: 5 met · 4 not met · 10 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.741T>G (p.Phe247Leu) variant has been observed in somatic cancer once in COSMIC and has been reported in ClinVar with an expert-panel Pathogenic classification.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population databases.
Within the BRAF RASopathy framework, this missense change lies in exon 6, a specified critical functional domain, and other expert-panel reviewed missense substitutions at the same codon, p.Phe247Val and p.Phe247Ser, have been classified as likely pathogenic.
Computational evidence supports a deleterious missense effect, with REVEL 0.816 exceeding the PP3 threshold of 0.7, while SpliceAI predicts no significant splice impact with a maximum delta score of 0.08.
No criteria match.
Met · 5
PM1 ModerateThis missense variant is located in BRAF exon 6, and the BRAF RASopathy specification lists exon 6 as a critical and well-established functional domain 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 normalization places c.741T>G / p.(Phe247Leu) in exon 6.
- The BRAF RASopathy specification states that PM1 is applicable to exon 6.
Sources
PM2 SupportingThis variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, which meets the BRAF RASopathy PM2 threshold of absence from controls. Details ▾Hide ▴
Rule
The variant must be absent from controls (gnomAD).
Evidence considered
- gnomAD v2.1: absent.
- gnomAD v4.1: absent.
- The BRAF RASopathy specification applies PM2 at supporting strength when the variant is absent from gnomAD.
Sources
PM5 ModerateOther missense changes at the same codon have been reported in ClinVar with expert-panel review, including p.(Phe247Val) and p.(Phe247Ser), both classified as likely pathogenic. This supports PM5 at moderate strength for a different missense change at the same residue. Details ▾Hide ▴
Rule
Moderate: 1 [likely] pathogenic residue change at the same codon.
Evidence considered
- ClinVar documents BRAF p.(Phe247Val) as likely pathogenic with expert-panel review.
- ClinVar documents BRAF p.(Phe247Ser) as likely pathogenic with expert-panel review.
- The BRAF RASopathy specification allows PM5 moderate for one likely pathogenic/pathogenic residue change at the same codon and strong for two different such changes observed in at least 5 probands.
Still missing
- The reviewed evidence did not provide proband counts needed to consider PM5_Strong.
Sources
PP3 SupportingComputational evidence supports a deleterious missense effect. REVEL is 0.816, which is above the BRAF RASopathy PP3 threshold of 0.7, while SpliceAI predicts no significant splice impact with a maximum delta score of 0.08, supporting a protein-level rather than splice-driven effect. Details ▾Hide ▴
Rule
For missense variants: REVEL >= 0.7. For splicing impact, predicted outcome must match disease mechanism.
Evidence considered
- REVEL score: 0.816.
- SpliceAI max delta score: 0.08.
- BayesDel score: 0.227743.
- The BRAF RASopathy specification applies PP3 for missense variants with REVEL >=0.7.
Sources
Not met · 4 · evaluated, threshold not reached
PS1 No previously established pathogenic variant producing the same amino acid change, p.(Phe247Leu), by a different nucleotide change was identified in the reviewed sources, so PS1 is not met. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Evidence considered
- PS1 requires the same amino acid change as a previously established pathogenic variant.
- The reviewed sources document this specific p.(Phe247Leu) variant but did not identify a different nucleotide change producing the same amino acid substitution.
Still missing
- A definitive same-amino-acid comparator review across all curated sources was not available in the reviewed materials.
Sources
BA1 This variant is absent from gnomAD v2.1 and v4.1, so it does not meet the BA1 population threshold of filtering allele frequency at or above 0.05%. Details ▾Hide ▴
Rule
GnomAD filtering allele frequency >=0.05%.
Evidence considered
- gnomAD v2.1: absent.
- gnomAD v4.1: absent.
- BA1 requires filtering allele frequency >=0.05%.
Sources
BS1 This variant is absent from gnomAD v2.1 and v4.1, so it does not meet the BS1 population threshold of filtering allele frequency at or above 0.025%. Details ▾Hide ▴
Rule
GnomAD filtering allele frequency >=0.025%.
Evidence considered
- gnomAD v2.1: absent.
- gnomAD v4.1: absent.
- BS1 requires filtering allele frequency >=0.025%.
Sources
BP4 Available computational evidence does not support BP4 for a benign missense effect. REVEL is 0.816, which is above the benign threshold of 0.3, although SpliceAI predicts no significant splice impact with a maximum delta score of 0.08. Details ▾Hide ▴
Rule
For missense variants: REVEL <= 0.3.
Evidence considered
- REVEL score: 0.816.
- SpliceAI max delta score: 0.08.
- BayesDel score: 0.227743.
- BP4 for missense variants requires REVEL <=0.3 in this framework.
Sources
Not assessed · 10 · no assessment recorded
PS2 No confirmed de novo occurrence with confirmed maternity and paternity was identified in the reviewed evidence, so PS2 cannot be applied at this time. Details ▾Hide ▴
Rule
Point-based de novo scoring; 4 points very strong, 2 points strong, 1 point moderate.
Evidence considered
- The BRAF RASopathy specification uses point-based de novo scoring for PS2.
- The reviewed evidence did not provide a confirmed de novo report for this variant.
Still missing
- Case-level inheritance data with confirmed maternity and paternity were not available.
- Affected-individual phenotype specificity and de novo point scoring were not documented in the reviewed sources.
Sources
PS3 Approved functional assay frameworks were identified for BRAF, but no directly reviewed variant-specific assay result for p.(Phe247Leu) was available here, so PS3 was not applied. Details ▾Hide ▴
Rule
Moderate requires two or more different approved assays; supporting requires one approved assay.
Evidence considered
- The BRAF RASopathy functional-study framework defines approved assay types and supports PS3 only when variant-specific approved assay evidence is available.
- OncoKB linked variant-relevant literature
- but the reviewed materials did not provide enough primary-study detail to independently score PS3 for this variant.
Still missing
- Direct variant-specific results from approved functional assays were not available in the reviewed materials.
- Underlying assay-level details for the OncoKB-linked publications were not sufficiently reviewed for this specific variant.
Sources
cspec ↗oncokb ↗vcep_svi_rasopathy_vcep_v2_approved_functional_studiesPMID:28512244 ↗PMID:29533785 ↗PMID:31515458 ↗
PS4 The variant is classified by an expert panel in ClinVar, but the reviewed evidence did not provide the case counts or point-based affected-individual data needed to score PS4 within the BRAF RASopathy framework. Details ▾Hide ▴
Rule
Point-based affected-individual scoring; 5 points strong, 3 points moderate, 1 point supporting.
Evidence considered
- The BRAF RASopathy specification scores PS4 using points.
- The reviewed evidence confirmed expert-panel ClinVar classification but did not provide the underlying point-generating case counts.
Still missing
- Exact unrelated affected case counts were not available.
- PS4 point scoring could not be calculated from the reviewed evidence.
Sources
PM6 No assumed de novo occurrence without confirmed parentage was identified in the reviewed evidence, so PM6 was not applied. Details ▾Hide ▴
Rule
Point-based scoring; 2 points strong, 1 point moderate, 0.5 point supporting.
Evidence considered
- The BRAF RASopathy specification uses point-based scoring for PM6.
- The reviewed evidence did not provide a usable assumed de novo report for this variant.
Still missing
- Case-level inheritance data without full parentage confirmation were not available.
- PM6 point scoring could not be calculated from the reviewed evidence.
Sources
PP1 No segregation data were identified for this variant, so PP1 cannot be applied. Details ▾Hide ▴
Rule
Supporting at >=3 informative meioses, moderate at >=5, strong at >=7.
Evidence considered
- The BRAF RASopathy specification applies PP1 using informative meioses.
- No segregation evidence was identified in the reviewed sources.
Still missing
- No pedigree or informative meiosis data were available.
Sources
PP2 This is a missense variant in BRAF, but the reviewed evidence did not provide the gene-level missense constraint value needed to determine whether the missense z score exceeds the BRAF RASopathy PP2 threshold. Details ▾Hide ▴
Rule
Missense z score is >3.09 in gnomAD.
Evidence considered
- The BRAF RASopathy specification applies PP2 when the missense z score is >3.09.
- The reviewed materials did not provide the missense z score needed for scoring.
Still missing
- Gene-level gnomAD missense z score was not available in the reviewed materials.
Sources
BS2 No evidence was identified showing this variant in unaffected individuals in numbers sufficient for BS2 scoring. Details ▾Hide ▴
Rule
-4 points strong; -1 point supporting.
Evidence considered
- The BRAF RASopathy specification uses point-based BS2 scoring.
- No unaffected-individual evidence was identified in the reviewed sources.
Still missing
- Unaffected carrier data were not available.
Sources
BS4 No lack-of-segregation evidence was identified for this variant, so BS4 cannot be applied. Details ▾Hide ▴
Rule
Requires only one informative meiosis.
Evidence considered
- The BRAF RASopathy specification allows BS4 with one informative meiosis.
- No family non-segregation evidence was identified in the reviewed sources.
Still missing
- Family-based non-segregation data were not available.
Sources
BP2 No evidence was identified for an alternative molecular explanation in cis or trans that would support BP2 scoring. Details ▾Hide ▴
Rule
-4 points strong; -2 points moderate; -1 point supporting.
Evidence considered
- The BRAF RASopathy specification uses point-based BP2 scoring.
- No qualifying molecular context for BP2 was identified.
Still missing
- Phase information and alternative-cause data were not available.
Sources
BP5 No evidence was identified for a fully explanatory alternative molecular diagnosis or a phenotype inconsistent with a RASopathy that would support BP5 scoring. Details ▾Hide ▴
Rule
-4 points strong; -2 points moderate; -1 point supporting.
Evidence considered
- The BRAF RASopathy specification uses point-based BP5 scoring.
- No qualifying alternative-diagnosis evidence was identified.
Still missing
- Alternative molecular diagnosis data and full phenotype data were not available.
Sources
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant, and the BRAF RASopathy specification marks PVS1 as not applicable for this gene framework. Details ▾Hide ▴
Evidence considered
- NM_001354609.1:c.741T>G predicts p.(Phe247Leu)
- a missense change.
- The reviewed PVS1 scaffold states that this variant does not fall into a null-variant category.
- The BRAF RASopathy specification lists PVS1 as not applicable.
Sources
PM3 N/APM3 is not applicable in this BRAF RASopathy framework. Details ▾Hide ▴
PM4 N/AThis is not an in-frame insertion, in-frame deletion, or stop-loss variant, so PM4 is not applicable to this missense change. Details ▾Hide ▴
Evidence considered
- p.(Phe247Leu) is a missense substitution.
- PM4 is reserved for protein length changes due to in-frame indels or stop-loss variants.
Sources
PP4 N/APP4 is not applicable in this BRAF RASopathy framework because phenotype-based weighting is incorporated through PS4. Details ▾Hide ▴
BS3 N/ABS3 is not applicable in this BRAF RASopathy framework. Details ▾Hide ▴
BP1 N/AThis criterion is reserved in the BRAF RASopathy framework for truncating variants in genes where gain-of-function missense variants are the relevant disease mechanism. It does not apply to this missense variant. Details ▾Hide ▴
Evidence considered
- The BRAF RASopathy specification restricts BP1 to truncating variants in the relevant context.
- p.(Phe247Leu) is a missense variant.
Sources
BP3 N/ABP3 is not applicable in this BRAF RASopathy framework. Details ▾Hide ▴
BP6 N/ABP6 is not used in this expert-panel framework. Details ▾Hide ▴
BP7 N/AThis is not a synonymous, intronic, or non-coding variant, so BP7 does not apply. Details ▾Hide ▴
Evidence considered
- p.(Phe247Leu) is a missense variant.
- BP7 is intended for synonymous or certain non-coding variants with no predicted splice impact.
Sources
Identifiers
- Gene
- BRAF
- Transcript
- NM_001354609.1
- Coding (HGVS c.)
- NM_001354609.1:c.741T>G
- Protein (HGVS p.)
- NP_001341538.1:p.(Phe247Leu)
- GRCh38
- chr7:140801531 A>C
- GRCh37
- chr7:140501331 A>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 SupportingComputational evidence supports a deleterious missense effect. REVEL is 0.816, which is above the BRAF RASopathy PP3 threshold of 0.7, while SpliceAI predicts no significant splice impact with a maximum delta score of 0.08, supporting a protein-level rather than splice-driven effect. Details ▾Hide ▴
Rule
For missense variants: REVEL >= 0.7. For splicing impact, predicted outcome must match disease mechanism.
Evidence considered
- REVEL score: 0.816.
- SpliceAI max delta score: 0.08.
- BayesDel score: 0.227743.
- The BRAF RASopathy specification applies PP3 for missense variants with REVEL >=0.7.
Sources
BP4 Available computational evidence does not support BP4 for a benign missense effect. REVEL is 0.816, which is above the benign threshold of 0.3, although SpliceAI predicts no significant splice impact with a maximum delta score of 0.08. Details ▾Hide ▴
Rule
For missense variants: REVEL <= 0.3.
Evidence considered
- REVEL score: 0.816.
- SpliceAI max delta score: 0.08.
- BayesDel score: 0.227743.
- BP4 for missense variants requires REVEL <=0.3 in this framework.
Sources
BP7 N/AThis is not a synonymous, intronic, or non-coding variant, so BP7 does not apply. Details ▾Hide ▴
Evidence considered
- p.(Phe247Leu) is a missense variant.
- BP7 is intended for synonymous or certain non-coding variants with no predicted splice impact.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.08). REVEL score = 0.816. BayesDel score = 0.227743.
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/55793/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/7-140501331-A-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr7-140801531-A-C?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/mutation/overview?id=189885933
- 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 (3 clinical laboratories) and as Likely pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen RASopathy Variant Curation Expert Panel (expert panel). (ClinVarID = 55793)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.08). REVEL score = 0.816. BayesDel score = 0.227743.
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 previously been reported in somatic cancers (COSMIC; COSV56165267, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.