About BRAF
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRAF c.722C>A, p.(Thr241Lys)
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, which is explicitly listed by the BRAF RASopathy specification as a critical and well-established functional region for PM1.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, meeting the RASopathy specification requirement that the variant be absent from controls for PM2_Supporting.
PM5Moderate
PM5 · moderate
A different missense change at the same residue, p.(Thr241Pro), is listed as pathogenic/likely pathogenic in the RASopathy VCEP approved functional-study materials, satisfying the BRAF same-codon PM5 rule for one established pathogenic or likely pathogenic residue change.
PP3Supporting
PP3 · supporting
Computational evidence supports a deleterious missense effect: REVEL is 0.946, which is above the BRAF RASopathy PP3 threshold of 0.7, BayesDel is 0.468035, and SpliceAI predicts no meaningful splice disruption (max delta score 0.04), supporting a protein-level rather than splice-mediated 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 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
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.722C>A (p.Thr241Lys) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar, including a Pathogenic expert-panel classification from the ClinGen RASopathy Variant Curation Expert Panel.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports rarity in reference populations.
A different missense change at the same residue, p.Thr241Pro, is listed as pathogenic/likely pathogenic in the RASopathy VCEP approved functional-study materials, supporting same-residue evidence under the BRAF specification.
Computational evidence supports a deleterious missense effect because REVEL is 0.946, above the BRAF PP3 threshold of 0.7, while SpliceAI predicts no significant splice impact with a maximum delta score of 0.04.
No criteria match.
Met · 5
PM1 ModerateThis missense variant is located in BRAF exon 6, which is explicitly listed by the BRAF RASopathy specification as a critical and well-established functional region 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 maps to exon 6
- BRAF VCEP lists exon 6 as PM1-eligible
Sources
PM2 SupportingThis variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, meeting the RASopathy specification requirement that the variant be absent from controls for PM2_Supporting. Details ▾Hide ▴
Rule
The variant must be absent from controls (gnomAD).
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
Sources
PM5 ModerateA different missense change at the same residue, p.(Thr241Pro), is listed as pathogenic/likely pathogenic in the RASopathy VCEP approved functional-study materials, satisfying the BRAF same-codon PM5 rule for one established pathogenic or likely pathogenic residue change. Details ▾Hide ▴
Rule
1 [likely] pathogenic residue change at the same codon.
Evidence considered
- Same-residue comparator p.(Thr241Pro) labeled P/LP in approved VCEP materials
Sources
cspec ↗vcep_svi_rasopathy_vcep_v2_approved_functional_studies
PP3 SupportingComputational evidence supports a deleterious missense effect: REVEL is 0.946, which is above the BRAF RASopathy PP3 threshold of 0.7, BayesDel is 0.468035, and SpliceAI predicts no meaningful splice disruption (max delta score 0.04), supporting a protein-level rather than splice-mediated effect. Details ▾Hide ▴
Rule
For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.
Evidence considered
- REVEL 0.946
- BayesDel 0.468035
- SpliceAI max delta 0.04
Sources
Not met · 4 · evaluated, threshold not reached
PS1 No evidence was identified that a different nucleotide change produces the same p.(Thr241Lys) amino acid substitution with an established pathogenic classification. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Evidence considered
- No same-amino-acid alternate nucleotide comparator identified
Still missing
- A confirmed alternate nucleotide change causing the same amino acid substitution was not identified.
Sources
BA1 This variant is absent from gnomAD and does not meet the BRAF RASopathy BA1 stand-alone benign frequency threshold of 0.05%. 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 and does not meet the BRAF RASopathy BS1 benign frequency threshold of 0.025%. Details ▾Hide ▴
Rule
GnomAD filtering allele frequency ≥0.025%.
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
Sources
BP4 Computational results do not support a benign interpretation for this missense change because REVEL is 0.946, which is above the benign BP4 threshold of 0.3. Details ▾Hide ▴
Rule
For missense variants: REVEL ≤0.3.
Evidence considered
- REVEL 0.946
- SpliceAI max delta 0.04
Sources
Not assessed · 10 · no assessment recorded
PS2 No parentage-confirmed de novo report for this exact variant was identified from the available evidence, so the point-based de novo criterion cannot be assigned here. Details ▾Hide ▴
Rule
Point-based de novo evidence; Strong at 2 points, Moderate at 1 point, Very Strong at 4 points.
Evidence considered
- No confirmed de novo evidence packet for p.(Thr241Lys)
Still missing
- Case-level parental testing details for the exact variant were not available.
- No de novo point total could be verified.
Sources
PS3 Published and curated functional materials were available for review, but no approved functional assay result for p.(Thr241Lys) itself was identified here, so PS3 cannot be assigned on the current evidence. Details ▾Hide ▴
Rule
Supporting for one approved assay; Moderate for two or more different approved assays.
Evidence considered
- Approved assay list reviewed
- No exact-variant approved assay result identified
Still missing
- Direct approved functional assay data for p.(Thr241Lys) were not identified.
Sources
PS4 This variant has been reported in ClinVar, including by the ClinGen RASopathy expert panel, but the available evidence does not provide the case counts or PS4 point total needed for the RASopathy point-based enrichment criterion. Details ▾Hide ▴
Rule
Point-based case enrichment; Supporting at 1 point, Moderate at 3 points, Strong at 5 points.
Evidence considered
- ClinVar expert panel classification present
- No PS4 point total documented
Still missing
- Independent proband counts and PS4 point assignment were not available.
Sources
PM6 No assumed de novo report with sufficient case-level detail for this exact variant was identified, so PM6 cannot be assigned from the current evidence. Details ▾Hide ▴
Rule
Point-based assumed de novo evidence; Supporting at 0.5 points, Moderate at 1 point, Strong at 2 points.
Evidence considered
- No PM6 point total or assumed de novo documentation identified
Still missing
- Case reports or submitter notes showing an assumed de novo occurrence were not available.
Sources
PP1 No segregation data were identified for this exact variant, so co-segregation evidence cannot be counted. Details ▾Hide ▴
Rule
Supporting at 3 informative meioses, Moderate at 5, Strong at 7.
Evidence considered
- No segregation evidence identified
Still missing
- Informative meioses were not available.
Sources
PP2 The BRAF RASopathy specification allows PP2 when the gnomAD missense z score is greater than 3.09, but a citable gene-level constraint value was not provided in the case materials, so this criterion is left for manual confirmation. Details ▾Hide ▴
Rule
Missense z score is >3.09 in gnomAD.
Evidence considered
- PP2 threshold defined by framework
Still missing
- A case-citable BRAF missense constraint value was not included in the available source registry.
Sources
BS2 No evidence was identified showing this variant in unaffected individuals at the point threshold required for BS2. Details ▾Hide ▴
Rule
Point-based unaffected observation criterion.
Evidence considered
- No BS2 point evidence identified
Still missing
- Unaffected carrier observations were not available.
Sources
BS4 No non-segregation data were identified for this variant, so BS4 cannot be applied. Details ▾Hide ▴
Rule
Requires only one informative meiosis.
Evidence considered
- No BS4 evidence identified
Still missing
- An informative meiosis showing lack of segregation was not available.
Sources
BP2 No phase or alternate-molecular-explanation data were identified to support BP2. Details ▾Hide ▴
Rule
Point-based BP2 criterion.
Evidence considered
- No BP2 evidence identified
Still missing
- Cis/trans data and BP2 point evidence were not available.
Sources
BP5 No evidence was identified for an alternate molecular explanation meeting the point threshold for BP5. Details ▾Hide ▴
Rule
Point-based alternate cause criterion.
Evidence considered
- No BP5 evidence identified
Still missing
- BP5 point-based evidence was not available.
Sources
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant and does not fall into the null-variant categories used for PVS1; the BRAF RASopathy specification also marks PVS1 as not applicable for this case. Details ▾Hide ▴
Evidence considered
- Missense change p.(Thr241Lys)
- Generic PVS1 scaffold does not place this variant in a PVS1 null-variant bucket
Sources
cspec ↗pvs1_variant_assessment
PM3 N/APM3 is not applicable in this BRAF RASopathy framework. Details ▾Hide ▴
PM4 N/AThis is a missense substitution and not a protein length-changing variant, so PM4 does not apply. Details ▾Hide ▴
Rule
Protein length changes in a non-repeat region.
Evidence considered
- Missense variant
Sources
PP4 N/APP4 is not applicable in this BRAF RASopathy framework. Details ▾Hide ▴
BS3 N/ABS3 is not applicable in this BRAF RASopathy framework. Details ▾Hide ▴
BP1 N/AThis is not a truncating or loss-of-function variant, so the BRAF RASopathy BP1 rule does not apply. Details ▾Hide ▴
Rule
Use for truncating variants in genes without established LOF correlation to disease in this framework.
Evidence considered
- Missense variant
Sources
BP3 N/ABP3 is not applicable in this BRAF RASopathy framework. Details ▾Hide ▴
BP6 N/ABP6 is not applicable in this BRAF RASopathy framework. Details ▾Hide ▴
BP7 N/AThis is not a synonymous, intronic, or non-coding variant, so BP7 does not apply. Details ▾Hide ▴
Rule
Silent or relevant non-coding variant with no predicted splice impact and no high conservation concern.
Evidence considered
- Missense variant
- SpliceAI max delta 0.04
Sources
Identifiers
- Gene
- BRAF
- Transcript
- NM_001354609.1
- Coding (HGVS c.)
- NM_001354609.1:c.722C>A
- Protein (HGVS p.)
- NP_001341538.1:p.(Thr241Lys)
- GRCh38
- chr7:140801550 G>T
- GRCh37
- chr7:140501350 G>T
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 0.946, which is above the BRAF RASopathy PP3 threshold of 0.7, BayesDel is 0.468035, and SpliceAI predicts no meaningful splice disruption (max delta score 0.04), supporting a protein-level rather than splice-mediated effect. Details ▾Hide ▴
Rule
For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.
Evidence considered
- REVEL 0.946
- BayesDel 0.468035
- SpliceAI max delta 0.04
Sources
BP4 Computational results do not support a benign interpretation for this missense change because REVEL is 0.946, which is above the benign BP4 threshold of 0.3. Details ▾Hide ▴
Rule
For missense variants: REVEL ≤0.3.
Evidence considered
- REVEL 0.946
- SpliceAI max delta 0.04
Sources
BP7 N/AThis is not a synonymous, intronic, or non-coding variant, so BP7 does not apply. Details ▾Hide ▴
Rule
Silent or relevant non-coding variant with no predicted splice impact and no high conservation concern.
Evidence considered
- Missense variant
- SpliceAI max delta 0.04
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.946. BayesDel score = 0.468035.
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/44829/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/7-140501350-G-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr7-140801550-G-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001354609.1%3Ac.7…
- OncoKB ↗www.oncokb.org/gene/BRAF/T241K
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRAF+c.722C%3EA
- 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 (1 clinical laboratory) and as Likely pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen RASopathy Variant Curation Expert Panel (expert panel). (ClinVarID = 44829)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.946. BayesDel score = 0.468035.
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.