About BRAF
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRAF c.793G>C, p.(Gly265Arg)
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 affects p.(Gly265Arg) in BRAF exon 6. The BRAF RASopathy specification explicitly recognizes exon 6 as a PM1 region, so PM1 is met at moderate strength even though this variant was not identified as a statistically significant cancer hotspot.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, which meets the BRAF RASopathy PM2 threshold requiring absence from controls.
PP2Supporting
PP2 · supporting
This is a missense variant in BRAF, and the observed missense constraint z score is 3.99, which is above the BRAF RASopathy PP2 threshold of 3.09. This supports PP2 at supporting strength.
PP3Supporting
PP3 · supporting
Computational evidence supports a damaging missense effect. REVEL is 0.917, which is above the BRAF RASopathy PP3 threshold of 0.7, BayesDel is 0.403109 in a deleterious direction, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, supporting interpretation as a missense rather than splicing effect.
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: 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.
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 · 5 not met · 9 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.793G>C (p.Gly265Arg) variant has been observed in somatic cancer once in COSMIC and has been reported in ClinVar with an expert panel likely pathogenic classification and additional pathogenic or likely pathogenic clinical laboratory submissions.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population reference datasets.
Computational evidence supports a damaging missense effect, with REVEL 0.917 above the BRAF RASopathy PP3 threshold of 0.7, BayesDel 0.403109 in a deleterious direction, and SpliceAI showing no significant predicted splice impact (maximum delta score 0.00).
No criteria match.
Met · 5
PM1 ModerateThis missense variant affects p.(Gly265Arg) in BRAF exon 6. The BRAF RASopathy specification explicitly recognizes exon 6 as a PM1 region, so PM1 is met at moderate strength even though this variant was not identified as a statistically significant cancer hotspot. Details ▾Hide ▴
Rule
PM1 Moderate for variants in specified BRAF regions including exon 6.
Evidence considered
- Variant localizes to exon 6
- BRAF RASopathy specification lists exon 6 as a PM1 region
- Cancer Hotspots did not show a significant hotspot
- which does not override the exon 6 VCEP rule
Sources
PM2 SupportingThis variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, which meets the BRAF RASopathy PM2 threshold requiring absence from controls. Details ▾Hide ▴
Rule
PM2 Supporting when the variant is absent from gnomAD.
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
Sources
PP2 SupportingThis is a missense variant in BRAF, and the observed missense constraint z score is 3.99, which is above the BRAF RASopathy PP2 threshold of 3.09. This supports PP2 at supporting strength. Details ▾Hide ▴
Rule
PP2 Supporting when missense z score is greater than 3.09 in gnomAD.
Evidence considered
- BRAF missense z score 3.99
- Threshold for PP2 is >3.09
Sources
PP3 SupportingComputational evidence supports a damaging missense effect. REVEL is 0.917, which is above the BRAF RASopathy PP3 threshold of 0.7, BayesDel is 0.403109 in a deleterious direction, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, supporting interpretation as a missense rather than splicing effect. Details ▾Hide ▴
Rule
PP3 Supporting for missense variants when REVEL is at least 0.7.
Evidence considered
- REVEL 0.917
- BayesDel 0.403109
- SpliceAI max delta 0.00
Sources
Not met · 5 · evaluated, threshold not reached
PS1 No alternate nucleotide change producing the same amino acid substitution was identified, so available evidence does not support PS1 for this variant. Details ▾Hide ▴
Rule
PS1 requires the same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Evidence considered
- ClinVar record identified for this exact variant
- No same-amino-acid alternate nucleotide evidence was identified
Still missing
- Direct review of any additional non-ClinVar exact amino-acid records could further confirm absence of an alternative nucleotide change.
Sources
PM5 No different pathogenic or likely pathogenic missense change at codon 265 was identified from the available evidence, so PM5 is not met. Details ▾Hide ▴
Rule
PM5 requires a different established pathogenic or likely pathogenic missense change at the same codon.
Evidence considered
- ClinVar exact-variant record reviewed
- No other codon-265 pathogenic missense change was identified in the available evidence
Still missing
- Additional codon-specific review outside the retrieved records could further confirm absence of another established pathogenic missense change at codon 265.
Sources
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its observed population frequency is 0%, which is below the BA1 threshold of 0.05%. BA1 is not met. Details ▾Hide ▴
Rule
BA1 requires gnomAD filtering allele frequency of at least 0.05%.
Evidence considered
- Observed population frequency 0% in gnomAD v2.1
- Observed population frequency 0% in gnomAD v4.1
- BA1 threshold 0.05%
Sources
BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its observed population frequency is 0%, which is below the BS1 threshold of 0.025%. BS1 is not met. Details ▾Hide ▴
Rule
BS1 requires gnomAD filtering allele frequency of at least 0.025%.
Evidence considered
- Observed population frequency 0% in gnomAD v2.1
- Observed population frequency 0% in gnomAD v4.1
- BS1 threshold 0.025%
Sources
BP4 Available computational evidence does not support BP4. REVEL is 0.917, which is above the benign BP4 threshold of 0.3, and BayesDel is also in a deleterious direction. Although SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, that does not override the missense prediction profile. Details ▾Hide ▴
Rule
BP4 Supporting for missense variants requires REVEL of 0.3 or lower.
Evidence considered
- REVEL 0.917
- BayesDel 0.403109
- SpliceAI max delta 0.00
- BP4 missense threshold REVEL <=0.3
Sources
Not assessed · 9 · no assessment recorded
PS2 No confirmed de novo occurrence with sufficient case-level phenotypic detail and parental confirmation was identified, so PS2 cannot be applied from the available evidence. Details ▾Hide ▴
Rule
PS2 uses the RASopathy point-based de novo framework.
Evidence considered
- ClinVar summary shows pathogenic and likely pathogenic submissions
- No usable de novo point-scoring evidence was identified
Still missing
- Case-level de novo reports
- Confirmation of maternity and paternity
- Phenotype detail sufficient for RASopathy point assignment
Sources
PS3 Approved BRAF functional assay frameworks are available, but no variant-specific result for p.(Gly265Arg) was identified in the retrieved materials. Available evidence therefore does not support PS3 at this time. Details ▾Hide ▴
Rule
PS3 requires one approved assay for supporting strength or two or more different approved assays for moderate strength.
Evidence considered
- RASopathy VCEP approved functional assay framework reviewed
- OncoKB did not identify variant-specific reviewed functional evidence
Still missing
- Variant-specific functional assay data for p.(Gly265Arg)
- Direct PMID-backed functional evidence using an approved assay
Sources
PS4 This variant is reported in ClinVar and has been observed once in COSMIC, but no case-count or case-control evidence meeting the RASopathy point-based PS4 framework was identified. PS4 is therefore not applied. Details ▾Hide ▴
Rule
PS4 in the RASopathy framework requires case-based point accumulation.
Evidence considered
- ClinVar expert panel and clinical laboratory submissions
- No statistically significant hotspot evidence identified
- No PS4 point-based case summary identified
Still missing
- Affected proband count meeting the RASopathy point framework
- Case-level phenotype and inheritance details
- Case-control enrichment or point-based evidence summary
Sources
PM6 No probable de novo observation with enough evidence for point assignment was identified, so PM6 cannot be applied from the available evidence. Details ▾Hide ▴
PP1 No segregation data or informative meiosis count was identified for this variant, so PP1 cannot be applied. Details ▾Hide ▴
BS2 No data were identified showing this variant in unaffected individuals at a level meeting the RASopathy BS2 point framework, so BS2 cannot be applied. Details ▾Hide ▴
Rule
BS2 uses the RASopathy point-based framework for unaffected observations.
Evidence considered
- No unaffected-carrier evidence identified
Still missing
- Unaffected carrier observations with enough detail for point assignment
Sources
BS4 No lack-of-segregation evidence in an informative family was identified, so BS4 cannot be applied. Details ▾Hide ▴
BP2 No evidence was identified for an alternative molecular explanation in cis or trans meeting the RASopathy BP2 point framework, so BP2 cannot be applied. Details ▾Hide ▴
Rule
BP2 uses the RASopathy point-based framework for alternative molecular explanations.
Evidence considered
- No qualifying BP2 molecular context identified
Still missing
- Case-level second-variant and phase data
Sources
BP5 No evidence was identified for a fully explanatory alternative molecular diagnosis or a phenotype inconsistency meeting the RASopathy BP5 point framework, so BP5 cannot be applied. Details ▾Hide ▴
Rule
BP5 uses the RASopathy point-based framework for alternative explanations.
Evidence considered
- No qualifying BP5 evidence identified
Still missing
- Alternative molecular diagnosis data
- Case-level phenotype data showing inconsistency with a RASopathy
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. The generic PVS1 assessment also indicates that this variant does not fall into a nonsense, frameshift, or canonical +/-1,2 splice category. Details ▾Hide ▴
Rule
PVS1 not applicable for this missense variant in the BRAF RASopathy framework.
Evidence considered
- BRAF RASopathy VCEP lists PVS1 as not applicable
- Generic PVS1 scaffold does not place this variant in a null-variant bucket
Sources
PM3 N/APM3 is not applicable in the BRAF RASopathy framework. Details ▾Hide ▴
Rule
PM3 not applicable.
Evidence considered
- BRAF RASopathy specification marks PM3 as not applicable
Sources
PM4 N/AThis is a missense substitution and does not cause a protein length change, so PM4 does not apply. Details ▾Hide ▴
Rule
PM4 applies to in-frame protein length changes or stop-loss variants.
Evidence considered
- Missense substitution without in-frame insertion
- deletion
- or stop-loss effect
Sources
PP4 N/APP4 is not applicable in the BRAF RASopathy framework because phenotype specificity is handled through other criteria such as PS4 and the de novo point-based framework. Details ▾Hide ▴
Rule
PP4 not applicable.
Evidence considered
- BRAF RASopathy specification marks PP4 as not applicable
Sources
BS3 N/ABS3 is not applicable in the BRAF RASopathy framework. Details ▾Hide ▴
Rule
BS3 not applicable.
Evidence considered
- BRAF RASopathy specification marks BS3 as not applicable
Sources
cspec ↗vcep_svi_rasopathy_vcep_v2_approved_functional_studies
BP1 N/ABP1 in this framework is used for truncating variants in a gain-of-function RASopathy gene without an established loss-of-function disease mechanism. This variant is missense, so BP1 does not apply. Details ▾Hide ▴
Rule
BP1 applies to qualifying truncating variants in this framework.
Evidence considered
- Missense variant rather than truncating variant
Sources
BP3 N/ABP3 is not applicable in the BRAF RASopathy framework. Details ▾Hide ▴
Rule
BP3 not applicable.
Evidence considered
- BRAF RASopathy specification marks BP3 as not applicable
Sources
BP6 N/ABP6 is not for use in this VCEP framework. Details ▾Hide ▴
Rule
BP6 not applicable.
Evidence considered
- BRAF RASopathy specification marks BP6 as not applicable
Sources
BP7 N/AThis is a missense variant, not a synonymous or qualifying intronic variant, so BP7 does not apply. Details ▾Hide ▴
Rule
BP7 applies to synonymous or qualifying intronic/non-coding variants with no predicted splice effect.
Evidence considered
- Missense variant
- BP7 is intended for synonymous or qualifying intronic/non-coding variants
Sources
Identifiers
- Gene
- BRAF
- Transcript
- NM_001354609.1
- Coding (HGVS c.)
- NM_001354609.1:c.793G>C
- Protein (HGVS p.)
- NP_001341538.1:p.(Gly265Arg)
- GRCh38
- chr7:140801479 C>G
- GRCh37
- chr7:140501279 C>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 damaging missense effect. REVEL is 0.917, which is above the BRAF RASopathy PP3 threshold of 0.7, BayesDel is 0.403109 in a deleterious direction, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, supporting interpretation as a missense rather than splicing effect. Details ▾Hide ▴
Rule
PP3 Supporting for missense variants when REVEL is at least 0.7.
Evidence considered
- REVEL 0.917
- BayesDel 0.403109
- SpliceAI max delta 0.00
Sources
BP4 Available computational evidence does not support BP4. REVEL is 0.917, which is above the benign BP4 threshold of 0.3, and BayesDel is also in a deleterious direction. Although SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, that does not override the missense prediction profile. Details ▾Hide ▴
Rule
BP4 Supporting for missense variants requires REVEL of 0.3 or lower.
Evidence considered
- REVEL 0.917
- BayesDel 0.403109
- SpliceAI max delta 0.00
- BP4 missense threshold REVEL <=0.3
Sources
BP7 N/AThis is a missense variant, not a synonymous or qualifying intronic variant, so BP7 does not apply. Details ▾Hide ▴
Rule
BP7 applies to synonymous or qualifying intronic/non-coding variants with no predicted splice effect.
Evidence considered
- Missense variant
- BP7 is intended for synonymous or qualifying intronic/non-coding variants
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.917. BayesDel score = 0.403109.
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/44832/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/7-140501279-C-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr7-140801479-C-G?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001354609.1%3Ac.7…
- OncoKB ↗www.oncokb.org/gene/BRAF/G265R
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=189930004
- 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 Likely pathogenic (2 clinical laboratories) and as Pathogenic (1 clinical laboratory) and as Likely pathogenic by ClinGen RASopathy Variant Curation Expert Panel (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.917. BayesDel score = 0.403109.
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 previously been reported in somatic cancers (COSMIC; COSV109420825, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.