About BRAF
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRAF c.1024A>G, p.(Ile342Val)
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: 0
Benign evidence criteria: 0
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
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: none; 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
92 / 1,613,958 alleles
gnomAD v4.1: 92 / 1,613,958 alleles. Recorded AF 5.70027e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.88937e-05; MAF= 0.00389%, 11/282822 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000138389; MAF= 0.01384%, 1/7226 alleles, homozygotes = 0); grpmax FAF= 1.685e-05.
No listed criterion applied
SpliceAI score
0.580 maximum delta
Recorded SpliceAI maximum delta score: 0.580. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
6 reported laboratory submissions
5 Uncertain significance · 1 Likely benign.
Context only
ClinVar ↗
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
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: 0 met · 8 not met · 10 not assessed · 10 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.1024A>G (p.Ile342Val) variant has been reported in ClinVar, where it is classified overall as a variant of uncertain significance, including by the ClinGen RASopathy Variant Curation Expert Panel, with one additional likely benign clinical laboratory submission.
This variant is present in gnomAD at low frequency, with an allele frequency of 0.00389% in v2.1 and 0.00570% in v4.1; these values are below the BRAF RASopathy BS1 threshold of 0.025% and BA1 threshold of 0.05%, but the variant is not absent from controls, so PM2 is not met.
No variant-specific result from an approved RASopathy VCEP functional assay was identified for p.Ile342Val, so functional evidence was insufficient to apply PS3.
Computational evidence is mixed: REVEL is 0.269 and BayesDel is -0.184306, which do not support a damaging missense effect, but SpliceAI predicts possible splice impact with a max delta score of 0.58; therefore, neither PP3 nor BP4 was applied.
No criteria match.
Not met · 8 · evaluated, threshold not reached
PS1 No previously established pathogenic variant causing the same amino acid change was identified in the available evidence, so PS1 is not met. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic variant, including analogous residues in BRAF/RAF1.
Evidence considered
- ClinVar contains the exact variant as Variation ID 359048
- No same-amino-acid pathogenic comparator was identified in the reviewed materials
Still missing
- A dedicated same-amino-acid comparison across BRAF and analogous RAF1 residues could be manually reconfirmed if needed.
Sources
PM1 The variant affects codon 342, which is outside the BRAF PM1-eligible regions listed in the RASopathy framework, including exon 6, exon 11, the P-loop (amino acids 459-474), and the CR3 activation segment (amino acids 594-627). Cancer Hotspots also did not identify this residue as a significant hotspot. Details ▾Hide ▴
Rule
PM1 applies only to specified BRAF functional domains/hotspots in the RASopathy framework.
Evidence considered
- Protein change p.(Ile342Val)
- CSPEC PM1 domains do not include residue 342
- Cancer Hotspots review did not show a significant hotspot at I342
Sources
PM2 This variant is present in population databases and therefore is not absent from controls. In gnomAD, the allele frequency is 0.00389% in v2.1 and 0.00570% in v4.1, so the RASopathy PM2 rule is not met. Details ▾Hide ▴
Rule
PM2 Supporting requires absence from gnomAD.
Evidence considered
- gnomAD v2.1 AF 0.00389% (11/282822)
- gnomAD v4.1 AF 0.00570% (92/1613958)
Sources
PM5 No different pathogenic or likely pathogenic missense change at the same residue was identified in the available evidence, so PM5 is not met. Details ▾Hide ▴
Rule
PM5 Moderate requires one pathogenic/likely pathogenic residue change at the same codon; PM5 Strong requires two different same-codon pathogenic changes observed in at least five probands.
Evidence considered
- No usable same-residue pathogenic comparator was identified in the reviewed materials
- PM5 candidate collection did not provide a qualifying comparator for codon 342
Still missing
- A manual codon-level review across BRAF and analogous RAF1 residues could be performed if additional comparator data become available
Sources
PP3 Available computational evidence does not meet the BRAF RASopathy PP3 rule. REVEL is 0.269, which is below the PP3 threshold of 0.7, and BayesDel is -0.184306, which does not support a damaging missense effect. Although SpliceAI predicts possible splice impact with a max delta score of 0.58, this alone does not satisfy the governing PP3 rule for this missense variant. Details ▾Hide ▴
Rule
For missense variants, PP3 requires REVEL ≥0.7; splice prediction must support a disease-mechanism-consistent effect.
Evidence considered
- REVEL 0.269
- BayesDel -0.184306
- SpliceAI max delta 0.58
Sources
BA1 The population frequency is below the BRAF RASopathy BA1 threshold. In gnomAD v4.1, the allele frequency is 0.00570%, which is below the 0.05% BA1 threshold. Details ▾Hide ▴
Rule
BA1 requires gnomAD filtering allele frequency ≥0.05%.
Evidence considered
- gnomAD v4.1 AF 0.00570% (92/1613958)
Sources
BS1 The population frequency is below the BRAF RASopathy BS1 threshold. In gnomAD v4.1, the allele frequency is 0.00570%, which is below the 0.025% BS1 threshold. Details ▾Hide ▴
Rule
BS1 requires gnomAD filtering allele frequency ≥0.025%.
Evidence considered
- gnomAD v4.1 AF 0.00570% (92/1613958)
Sources
BP4 Computational evidence is mixed and does not support applying BP4. REVEL is 0.269, which is within the BP4 threshold of 0.3 or lower, and BayesDel is -0.184306, which does not support a damaging missense effect; however, SpliceAI predicts possible splice impact with a max delta score of 0.58. Because the computational results are not uniformly benign, BP4 is not applied. Details ▾Hide ▴
Rule
For missense variants, BP4 uses REVEL ≤0.3; splice predictions should not indicate a disease-relevant effect.
Evidence considered
- REVEL 0.269
- BayesDel -0.184306
- SpliceAI max delta 0.58
Sources
Not assessed · 10 · no assessment recorded
PS2 No confirmed de novo occurrence with sufficient parental testing and phenotype detail was identified for this variant, so PS2 was not assessed. Details ▾Hide ▴
Rule
De novo points-based criterion under the RASopathy framework.
Evidence considered
- No de novo evidence was present in the reviewed ClinVar summary or retrieved case materials
Still missing
- No confirmed maternity/paternity data were identified
- No variant-specific de novo case report was identified
Sources
PS3 No variant-specific result from an approved functional assay was identified for p.(Ile342Val), so PS3 was not assessed. Details ▾Hide ▴
Rule
PS3 Supporting requires one approved assay; PS3 Moderate requires two or more different approved assays.
Evidence considered
- RASopathy VCEP functional studies workbook did not identify this variant among approved assay results
- OncoKB did not identify variant-specific reviewed functional evidence
Still missing
- No approved assay result specific to p.(Ile342Val) was identified
- Direct review of any future variant-specific functional publication would be needed
Sources
PS4 No exact-variant case series or case-count evidence showing enrichment in affected individuals was identified, so PS4 was not assessed. Details ▾Hide ▴
Rule
RASopathy framework points-based prevalence criterion.
Evidence considered
- ClinVar shows an expert-panel VUS rather than established affected-case enrichment
- No retrieved publication provided a usable PS4 point count
Still missing
- No variant-specific affected case count was identified
- No case-control or points-based case enrichment evidence was identified
Sources
PM6 No apparently de novo occurrence without confirmed parentage was identified for this variant, so PM6 was not assessed. Details ▾Hide ▴
Rule
De novo points-based criterion without confirmed parentage under the RASopathy framework.
Evidence considered
- No PM6-qualifying de novo evidence was present in the retrieved materials
Still missing
- No variant-specific de novo report without confirmed parentage was identified
Sources
PP1 No segregation data or informative meioses were identified for this variant, so PP1 was not assessed. Details ▾Hide ▴
PP2 PP2 was not assessed because a BRAF missense constraint value meeting the framework threshold was not identified in the reviewed evidence. Details ▾Hide ▴
Rule
Missense z score >3.09 in gnomAD.
Evidence considered
- CSPEC PP2 requires missense z score >3.09 in gnomAD
Still missing
- No retrieved BRAF missense z score was available for confirmation against the >3.09 threshold
Sources
BS2 No evidence was identified showing this variant in a sufficient number of unaffected individuals to meet the points-based BS2 rule, so BS2 was not assessed. Details ▾Hide ▴
Rule
Points-based unaffected observation criterion in the RASopathy framework.
Evidence considered
- Population counts were available
- but no BS2-specific unaffected-carrier assessment was provided
Still missing
- No penetrance-aware unaffected carrier data were identified
Sources
BS4 No family data showing lack of segregation were identified for this variant, so BS4 was not assessed. Details ▾Hide ▴
BP2 No phase data or observation with another pathogenic variant were identified, so BP2 was not assessed. Details ▾Hide ▴
Rule
Points-based allelic criterion in the RASopathy framework.
Evidence considered
- No BP2-relevant allelic data were present in the reviewed materials
Still missing
- No cis/trans phase information was identified
- No points-based BP2 evidence was available
Sources
BP5 No alternate molecular explanation or points-based BP5 evidence was identified for this variant, so BP5 was not assessed. Details ▾Hide ▴
Rule
Points-based alternate-cause criterion in the RASopathy framework.
Evidence considered
- No BP5-specific case data were present in the reviewed materials
Still missing
- No BP5-relevant alternate diagnosis data were identified
Sources
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 VCEPThis variant is a missense substitution, and the BRAF RASopathy framework marks PVS1 as not applicable. The generic PVS1 scaffold also indicates that c.1024A>G does not fall into a null-variant category such as nonsense, frameshift, or canonical splice-site loss. Details ▾Hide ▴
VCEP rule
PVS1 not applicable for this missense variant in the governing framework.
Evidence considered
- BRAF RASopathy CSPEC lists PVS1 as not applicable
- pvs1_variant_assessment identifies this variant as non-null and outside generic PVS1 buckets
Sources
PM3 VCEPPM3 is not applicable in this BRAF RASopathy framework. Details ▾Hide ▴
VCEP rule
Not applicable in governing framework.
Evidence considered
- CSPEC marks PM3 as not applicable
Sources
PM4 N/AThis is a single amino acid substitution and does not change protein length, so PM4 is not applicable. Details ▾Hide ▴
Rule
PM4 addresses protein length changes, not missense substitutions.
Evidence considered
- Protein consequence p.(Ile342Val) is missense
- not an in-frame indel or stop-loss
Sources
PP4 VCEPPP4 is not applicable in this BRAF RASopathy framework. Details ▾Hide ▴
VCEP rule
Not applicable in governing framework.
Evidence considered
- CSPEC marks PP4 as not applicable
Sources
PP5 VCEPPP5 is not applicable in this BRAF RASopathy framework. Details ▾Hide ▴
VCEP rule
Not applicable in governing framework.
Evidence considered
- CSPEC marks PP5 as not applicable
Sources
BS3 VCEPBS3 is not applicable in this BRAF RASopathy framework. Details ▾Hide ▴
VCEP rule
Not applicable in governing framework.
Evidence considered
- CSPEC marks BS3 as not applicable
Sources
BP1 N/AThis is a missense variant, whereas BP1 in the RASopathy framework is reserved for truncating variants in genes where gain-of-function missense variants are the established mechanism. Details ▾Hide ▴
Rule
RASopathy-adapted BP1 applies to truncating variants, not missense substitutions.
Evidence considered
- Protein consequence is missense
- CSPEC BP1 usage is restricted to truncating variants in this framework
Sources
BP3 VCEPBP3 is not applicable in this BRAF RASopathy framework. Details ▾Hide ▴
VCEP rule
Not applicable in governing framework.
Evidence considered
- CSPEC marks BP3 as not applicable
Sources
BP6 VCEPBP6 is not applicable in this BRAF RASopathy framework. Details ▾Hide ▴
VCEP rule
Not applicable in governing framework.
Evidence considered
- CSPEC marks BP6 as not applicable
Sources
BP7 N/AThis is a missense variant, not a synonymous or intronic change, so BP7 is not applicable. Details ▾Hide ▴
Rule
BP7 applies to synonymous, intronic, or other non-coding variants without predicted splice impact.
Evidence considered
- Protein consequence p.(Ile342Val) is missense
Sources
Identifiers
- Gene
- BRAF
- Transcript
- NM_001354609.1
- Coding (HGVS c.)
- NM_001354609.1:c.1024A>G
- Protein (HGVS p.)
- NP_001341538.1:p.(Ile342Val)
- GRCh38
- chr7:140794424 T>C
- GRCh37
- chr7:140494224 T>C
- ClinVar
- 359048
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
92 / 1,613,958 alleles
AF 5.7e-05 · 0 homozygotes · FAF 5.19e-05
gnomAD v2.1
11 / 282,822 alleles
AF 3.89e-05 · 0 homozygotes · FAF 1.69e-05
By genetic ancestry
gnomAD v4.1
AF 5.7e-05 · 92 / 1,613,958 alleles · 0 hom · FAF 5.2e-05
| Remaining individuals6 / 62,502 | 9.6e-05 |
| African/African American7 / 74,956 | 9.3e-05 |
| European (non-Finnish)75 / 1,179,980 | 6.4e-05 |
| Admixed American2 / 60,010 | 3.3e-05 |
| East Asian1 / 44,874 | 2.2e-05 |
| South Asian1 / 91,068 | 1.1e-05 |
0 alternate alleles recorded in 4 other groups: European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish.
gnomAD v2.1
AF 3.9e-05 · 11 / 282,822 alleles · 0 hom · FAF 1.7e-05
| Remaining individuals1 / 7,226 | 0.00014 |
| Admixed American2 / 35,438 | 5.6e-05 |
| European (non-Finnish)6 / 129,154 | 4.6e-05 |
| African/African American1 / 24,958 | 4e-05 |
| South Asian1 / 30,616 | 3.3e-05 |
0 alternate alleles recorded in 3 other groups: Ashkenazi Jewish, East Asian, European (Finnish).
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 5.70027e-05; MAF= 0.00570%, 92/1613958 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 9.59969e-05; MAF= 0.00960%, 6/62502 alleles, homozygotes = 0); grpmax FAF= 5.192e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.88937e-05; MAF= 0.00389%, 11/282822 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000138389; MAF= 0.01384%, 1/7226 alleles, homozygotes = 0); grpmax FAF= 1.685e-05.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.269
- BayesDel
- -0.184
How the predictions were used
PP3 Available computational evidence does not meet the BRAF RASopathy PP3 rule. REVEL is 0.269, which is below the PP3 threshold of 0.7, and BayesDel is -0.184306, which does not support a damaging missense effect. Although SpliceAI predicts possible splice impact with a max delta score of 0.58, this alone does not satisfy the governing PP3 rule for this missense variant. Details ▾Hide ▴
Rule
For missense variants, PP3 requires REVEL ≥0.7; splice prediction must support a disease-mechanism-consistent effect.
Evidence considered
- REVEL 0.269
- BayesDel -0.184306
- SpliceAI max delta 0.58
Sources
BP4 Computational evidence is mixed and does not support applying BP4. REVEL is 0.269, which is within the BP4 threshold of 0.3 or lower, and BayesDel is -0.184306, which does not support a damaging missense effect; however, SpliceAI predicts possible splice impact with a max delta score of 0.58. Because the computational results are not uniformly benign, BP4 is not applied. Details ▾Hide ▴
Rule
For missense variants, BP4 uses REVEL ≤0.3; splice predictions should not indicate a disease-relevant effect.
Evidence considered
- REVEL 0.269
- BayesDel -0.184306
- SpliceAI max delta 0.58
Sources
BP7 N/AThis is a missense variant, not a synonymous or intronic change, so BP7 is not applicable. Details ▾Hide ▴
Rule
BP7 applies to synonymous, intronic, or other non-coding variants without predicted splice impact.
Evidence considered
- Protein consequence p.(Ile342Val) is missense
Sources
Statement
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.58). REVEL score = 0.269. BayesDel score = -0.184306.
10 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
-
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 29398453 ↗Updated Molecular Testing Guideline for the Selection of Lung Cancer Patients for Treatment With Targeted Tyrosine Kinase Inhibitors: Guideline From the College of American Pathologists, the International Association for the Study of Lung Cancer, 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 ↗Cardiofaciocutaneous Syndrome.Adam MP et al. · 1993No paper-specific finding is recorded.
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PMID 20301390 ↗PMID:20301390No paper-specific finding is recorded.
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PMID 20301557 ↗Noonan Syndrome with Multiple Lentigines.Adam MP et al. · 1993No 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 25394175 ↗A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.No 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
92 / 1,613,958 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.580
Open source ↗
ClinVar
5 Uncertain significance · 1 Likely benign
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/359048/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/7-140494224-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr7-140794424-T-C?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001354609.1%3Ac.1…
- OncoKB ↗www.oncokb.org/gene/BRAF/I342V
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRAF+c.1024A%3EG
- 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
This variant is present in gnomAD v4.1 (AF= 5.70027e-05; MAF= 0.00570%, 92/1613958 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 9.59969e-05; MAF= 0.00960%, 6/62502 alleles, homozygotes = 0); grpmax FAF= 5.192e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.88937e-05; MAF= 0.00389%, 11/282822 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000138389; MAF= 0.01384%, 1/7226 alleles, homozygotes = 0); grpmax FAF= 1.685e-05.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (5 clinical laboratories) and as Likely benign (1 clinical laboratory) and as Uncertain significance by ClinGen RASopathy Variant Curation Expert Panel (expert panel). (ClinVarID = 359048)
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.58). REVEL score = 0.269. BayesDel score = -0.184306.
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.