About BRAF
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRAF c.730A>C, p.(Thr244Pro)
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: 4
Benign evidence criteria: 0
Pathogenic criteria applied · 4
PM1Moderate
PM1 · moderate
This missense variant affects BRAF exon 6, which is a critical and well-established region specifically listed by the RASopathy VCEP for PM1 application.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which meets the RASopathy VCEP PM2 threshold requiring absence from controls.
PP3Supporting
PP3 · supporting
Computational evidence supports a deleterious missense effect. REVEL is 0.855, which is above the RASopathy VCEP PP3 threshold of 0.7; BayesDel is also positive at 0.418359. SpliceAI predicts no major splice effect with a maximum delta score of 0.09, so the computational signal is consistent with a missense rather than splice mechanism.
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, 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 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: 4 met · 3 not met · 12 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.730A>C (p.Thr244Pro) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as Pathogenic, including an expert panel Pathogenic classification.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population controls.
This missense change affects BRAF exon 6, a region specified by the RASopathy VCEP for PM1, and computational evidence supports a deleterious missense effect with REVEL 0.855, BayesDel 0.418359, and no major predicted splice effect by SpliceAI (maximum delta score 0.09).
No criteria match.
Met · 4
PM1 ModerateThis missense variant affects BRAF exon 6, which is a critical and well-established region specifically listed by the RASopathy VCEP 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, CR3 activation segment).
Evidence considered
- Variant protein consequence p.(Thr244Pro)
- Variant maps to exon 6
- BRAF VCEP PM1 lists exon 6 as eligible region
Sources
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1, which meets the RASopathy VCEP PM2 threshold requiring absence from 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
PP3 SupportingComputational evidence supports a deleterious missense effect. REVEL is 0.855, which is above the RASopathy VCEP PP3 threshold of 0.7; BayesDel is also positive at 0.418359. SpliceAI predicts no major splice effect with a maximum delta score of 0.09, so the computational signal is consistent with a missense rather than splice mechanism. Details ▾Hide ▴
Rule
For missense variants: REVEL ≥0.7. For splicing impact, predicted outcome must match disease mechanism.
Evidence considered
- REVEL 0.855
- BayesDel 0.418359
- SpliceAI max delta 0.09
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 gnomAD v4.1, which is well below the 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 gnomAD v4.1, which is below the 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 Benign computational evidence is not supported. REVEL is 0.855, which is above the BP4 benign threshold of 0.3 for missense variants. Although SpliceAI predicts no major splice effect with a maximum delta score of 0.09, the missense prediction does not support a benign interpretation. Details ▾Hide ▴
Rule
For missense variants: REVEL ≤0.3.
Evidence considered
- REVEL 0.855
- SpliceAI max delta 0.09
Sources
Not assessed · 12 · no assessment recorded
PS1 No evidence was identified that this variant produces the same amino acid change as a previously established pathogenic variant through a different nucleotide change, including the analogous BRAF/RAF1 provision in the RASopathy VCEP rules. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic variant; applicable for analogous BRAF/RAF1 positions.
Evidence considered
- PS1 rule reviewed in BRAF RASopathy VCEP specification
Still missing
- Direct confirmation of any alternate nucleotide change producing the same pathogenic amino acid substitution was not identified in the retrieved evidence.
Sources
PS2 Published germline reports are linked for this variant, but the retrieved evidence does not provide case-level confirmation of de novo occurrence with confirmed maternity and paternity required for PS2 point assignment. Details ▾Hide ▴
Rule
RASopathy VCEP de novo point system: 4 points Very Strong, 2 Strong, 1 Moderate.
Evidence considered
- ClinVar Pathogenic
- expert panel reviewed
- Literature linked for de novo/clinical observation
Still missing
- No confirmed de novo case with parentage confirmation was identified in the retrieved evidence.
- No point-based PS2 total could be assigned from the available case-level details.
Sources
PS3 The RASopathy VCEP-approved functional study materials were reviewed, but no variant-specific approved assay result for p.(Thr244Pro) was identified in the retrieved evidence to support PS3 assignment. Details ▾Hide ▴
Rule
Two or more different approved assays = Moderate; one approved assay = Supporting.
Evidence considered
- VCEP-approved functional study summary reviewed
- No exact p.(Thr244Pro) assay result retrieved
Still missing
- Direct variant-specific approved functional assay data for p.(Thr244Pro) were not identified.
- A full publication-level review would be needed if additional functional data exist outside the retrieved summary materials.
Sources
cspec ↗vcep_svi_rasopathy_vcep_v2_approved_functional_studiesPMID:18413255 ↗PMID:22142829 ↗PMID:24033266 ↗184132552214282924033266
PS4 This variant has been reported in ClinVar, including an expert panel Pathogenic classification, but the retrieved evidence does not provide the independent affected-case counts or point total required for RASopathy VCEP PS4 scoring. Details ▾Hide ▴
Rule
RASopathy VCEP PS4 point system: 5 points Strong, 3 Moderate, 1 Supporting.
Evidence considered
- ClinVar Pathogenic
- expert panel reviewed
- Multiple linked publications
Still missing
- No PS4 point total could be calculated from the retrieved evidence.
- Independent affected-case counting and deduplication were not available in the reviewed materials.
Sources
cspec ↗clinvar ↗PMID:17551924 ↗PMID:18042262 ↗PMID:18413255 ↗PMID:19206169 ↗PMID:19416762 ↗PMID:22142829 ↗PMID:24033266 ↗PMID:27521173 ↗1755192418042262184132551920616919416762221428292403326627521173
PM5 No different pathogenic or likely pathogenic missense change at codon 244 was identified in the retrieved evidence, so PM5 could not be assigned from the materials reviewed. Details ▾Hide ▴
Rule
One pathogenic/likely pathogenic residue change at the same codon = Moderate; two different changes at the same codon observed in ≥5 probands = Strong.
Evidence considered
- PM5 codon-based rule reviewed
- No codon 244 alternate pathogenic substitution identified in retrieved evidence
Still missing
- Direct codon-level review for other pathogenic substitutions at residue 244 was not established in the retrieved evidence.
Sources
PM6 Published germline reports are linked for this variant, but the retrieved evidence does not document an assumed or confirmed de novo occurrence with enough case-level detail to assign PM6 points. Details ▾Hide ▴
Rule
RASopathy VCEP de novo point system: 2 points Strong, 1 Moderate, 0.5 Supporting.
Evidence considered
- ClinVar Pathogenic
- expert panel reviewed
- Literature linked for clinical case reports
Still missing
- No apparently de novo case without full parentage confirmation was identified in the retrieved evidence.
- No PM6 point total could be assigned from the available case-level details.
Sources
PP1 No segregation data were identified showing this variant co-segregates with a RASopathy phenotype across informative meioses. Details ▾Hide ▴
Rule
Supporting ≥3 informative meioses; Moderate ≥5; Strong ≥7.
Evidence considered
- PP1 segregation rule reviewed
Still missing
- No informative meioses were identified for this variant.
Sources
PP2 This is a missense variant in a gene where missense variation is clinically relevant, but the retrieved evidence does not provide the gnomAD missense z score needed for the BRAF RASopathy VCEP PP2 threshold (>3.09). Details ▾Hide ▴
Rule
Missense z score is >3.09 in gnomAD.
Evidence considered
- PP2 threshold reviewed in BRAF VCEP
Still missing
- Gene-level missense z score was not present in the retrieved evidence.
Sources
BS2 No evidence was identified that this variant is present in unaffected individuals at a level that would contribute benign evidence under the RASopathy point-based framework. Details ▾Hide ▴
Rule
Point-based benign evidence from observations in unaffected individuals.
Still missing
- No unaffected-carrier data were identified.
BS4 No family data were identified showing lack of segregation of this variant with disease. Details ▾Hide ▴
Rule
Requires only one informative meiosis.
Evidence considered
- BS4 segregation rule reviewed
Still missing
- No informative non-segregation data were identified.
Sources
BP2 No evidence was identified that this variant occurs with another pathogenic RASopathy variant in a configuration that would support BP2 points. Details ▾Hide ▴
Rule
Points awarded for an alternative molecular cause in the same gene and compatible phenotype.
Evidence considered
- BP2 point-based rule reviewed
Still missing
- No phase data or alternative same-gene molecular explanation was identified.
Sources
BP5 No alternative molecular diagnosis or non-RASopathy explanation was identified that would support BP5 points. Details ▾Hide ▴
Rule
Points awarded for an alternative molecular cause in a different gene or for a phenotype fully explained by another cause.
Evidence considered
- BP5 point-based rule reviewed
Still missing
- No alternate causative variant or clearly discordant phenotype explanation was identified.
Sources
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis variant is a missense substitution, and the BRAF RASopathy VCEP does not apply PVS1 to this variant type. The generic PVS1 scaffold also does not apply because this variant is not a nonsense, frameshift, or canonical splice-site variant. Details ▾Hide ▴
Rule
Not applicable for this VCEP; generic null-variant framework not triggered.
Evidence considered
- Missense variant p.(Thr244Pro)
- VCEP marks PVS1 not applicable
- Generic PVS1 scaffold not triggered
Sources
PM3 N/APM3 is not applicable because the BRAF RASopathy framework is not using a recessive trans-with-pathogenic-variant model for this condition. Details ▾Hide ▴
PM4 N/APM4 is not applicable because this variant is a missense substitution and does not change protein length through an in-frame insertion, in-frame deletion, or stop-loss event. Details ▾Hide ▴
Rule
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
Evidence considered
- Missense variant p.(Thr244Pro)
Sources
PP4 N/APP4 is not applicable in this RASopathy VCEP framework because phenotype-specific evidence is handled through PS4 rather than PP4. Details ▾Hide ▴
BS3 N/ABS3 is not applicable in this BRAF RASopathy VCEP framework. Details ▾Hide ▴
BP1 N/AThis criterion is reserved in the RASopathy framework for truncating or other loss-of-function variants in genes where gain-of-function missense variation is the relevant disease mechanism. This variant is a missense substitution, so BP1 does not apply. Details ▾Hide ▴
Rule
Use for truncating/LOF variants in genes without established LOF correlation to disease.
Evidence considered
- Missense variant p.(Thr244Pro)
- BP1 framework limited to truncating/LOF variant types
Sources
BP3 N/ABP3 is not applicable in this BRAF RASopathy VCEP framework. Details ▾Hide ▴
BP6 N/ABP6 is not applicable because this criterion is not used by the ClinGen Sequence Variant Interpretation VCEP Review Committee in the BRAF RASopathy framework. Details ▾Hide ▴
Rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
- BRAF VCEP marks BP6 not applicable
Sources
BP7 N/ABP7 does not apply because this variant is not synonymous or intronic; it is a missense substitution. Details ▾Hide ▴
Rule
Applicable to synonymous or certain intronic/non-coding variants with no predicted splice impact and low conservation.
Evidence considered
- Missense variant p.(Thr244Pro)
Sources
Identifiers
- Gene
- BRAF
- Transcript
- NM_001354609.1
- Coding (HGVS c.)
- NM_001354609.1:c.730A>C
- Protein (HGVS p.)
- NP_001341538.1:p.(Thr244Pro)
- GRCh38
- chr7:140801542 T>G
- GRCh37
- chr7:140501342 T>G
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 0.855, which is above the RASopathy VCEP PP3 threshold of 0.7; BayesDel is also positive at 0.418359. SpliceAI predicts no major splice effect with a maximum delta score of 0.09, so the computational signal is consistent with a missense rather than splice mechanism. Details ▾Hide ▴
Rule
For missense variants: REVEL ≥0.7. For splicing impact, predicted outcome must match disease mechanism.
Evidence considered
- REVEL 0.855
- BayesDel 0.418359
- SpliceAI max delta 0.09
Sources
BP4 Benign computational evidence is not supported. REVEL is 0.855, which is above the BP4 benign threshold of 0.3 for missense variants. Although SpliceAI predicts no major splice effect with a maximum delta score of 0.09, the missense prediction does not support a benign interpretation. Details ▾Hide ▴
Rule
For missense variants: REVEL ≤0.3.
Evidence considered
- REVEL 0.855
- SpliceAI max delta 0.09
Sources
BP7 N/ABP7 does not apply because this variant is not synonymous or intronic; it is a missense substitution. Details ▾Hide ▴
Rule
Applicable to synonymous or certain intronic/non-coding variants with no predicted splice impact and low conservation.
Evidence considered
- Missense variant p.(Thr244Pro)
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.09). REVEL score = 0.855. BayesDel score = 0.418359.
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/40346/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/7-140501342-T-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr7-140801542-T-G?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001354609.1%3Ac.7…
- OncoKB ↗www.oncokb.org/gene/BRAF/T244P
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRAF+c.730A%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 Pathogenic by ClinGen RASopathy Variant Curation Expert Panel (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.09). REVEL score = 0.855. BayesDel score = 0.418359.
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.