About BRAF
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRAF c.622A>G, p.(Ile208Val)
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: 1
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 1
BS2Supporting
BS2 · supporting
Published case-level evidence describes at least three phenotyped individuals without evidence of a RASopathy who carried this variant, including an unaffected father in the prenatal family. This supports BS2 at a conservative supporting level.
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: BS2 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
24 / 1,612,526 alleles
gnomAD v4.1: 24 / 1,612,526 alleles. Recorded AF 1.48835e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.4158e-05; MAF= 0.00142%, 4/282526 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.10236e-05; MAF= 0.00310%, 4/128934 alleles, homozygotes = 0); grpmax FAF= 7.02e-06.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
No listed criterion applied
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
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
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: 1 met · 14 not met · 3 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.622A>G (p.Ile208Val) variant has been reported in ClinVar with mostly likely benign laboratory submissions and an expert-panel uncertain significance classification, and published case-level data describe unaffected carriers and multiple individuals without findings consistent with a RASopathy.
This variant is present in population databases at low frequency, including 4/282526 alleles in gnomAD v2.1 (0.00142%) and 24/1612526 alleles in gnomAD v4.1 (0.00149%), which is below the BRAF RASopathy BS1 threshold of 0.025% and below the BA1 threshold of 0.05%, but means PM2 is not met because the variant is not absent from controls.
No approved variant-specific functional study was identified for p.Ile208Val in the reviewed RASopathy functional-study materials.
Computational evidence does not meet the VCEP missense thresholds: REVEL is 0.318, which is below the PP3 cutoff of 0.7 but above the BP4 cutoff of 0.3, while SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.01; the BayesDel score is -0.174758.
No criteria match.
Met · 1
BS2 SupportingPublished case-level evidence describes at least three phenotyped individuals without evidence of a RASopathy who carried this variant, including an unaffected father in the prenatal family. This supports BS2 at a conservative supporting level. Details ▾Hide ▴
Rule
BS2 uses the RASopathy benign point system; conservative assignment here is supporting.
Evidence considered
- Unaffected heterozygous father
- At least three phenotyped individuals without a RASopathy reported in the publication
Still missing
- The exact current VCEP point assignment for these unaffected observations was not directly recoverable from the reviewed files.
Sources
Not met · 14 · evaluated, threshold not reached
PS2 Available evidence does not support a confirmed de novo occurrence. In a published report, this variant was detected in an unaffected father, which does not meet the de novo requirement. Details ▾Hide ▴
Rule
PS2 requires de novo occurrence scored under the RASopathy point system.
Evidence considered
- Prenatal case with paternal inheritance
- No confirmed de novo observation identified
Still missing
- No independent confirmed de novo case with maternity and paternity confirmation was identified.
Sources
PS3 No approved variant-specific functional assay result was identified for p.Ile208Val. The reviewed RASopathy functional-study materials did not show this variant in an approved assay set. Details ▾Hide ▴
Rule
PS3_Supporting requires one approved assay; PS3_Moderate requires two or more different approved assays.
Evidence considered
- RASopathy approved functional studies workbook reviewed
- No variant-specific functional evidence identified
Still missing
- Direct review of any newly published functional assays would be needed if such data emerge.
Sources
PS4 Available evidence does not show enrichment of this variant in affected individuals. Published case-level data instead include unaffected carriers and individuals without findings consistent with a RASopathy. Details ▾Hide ▴
Rule
PS4 uses the RASopathy point-based case-enrichment framework.
Evidence considered
- Published unaffected carriers
- No affected-case point total recoverable for PS4
Still missing
- No case-enrichment or point-based affected observation dataset meeting the VCEP threshold was identified.
Sources
PM1 This variant is in exon 5, while the BRAF RASopathy specification limits PM1 to exon 6, exon 11, the P-loop (amino acids 459-474), or the CR3 activation segment (amino acids 594-627). No hotspot evidence was identified for codon 208. Details ▾Hide ▴
Rule
PM1 applicable only to exon 6, exon 11, P-loop AA 459-474, or CR3 activation segment AA 594-627.
Evidence considered
- Variant localizes to exon 5
- Cancer Hotspots review did not identify a hotspot row for I208
Sources
PM2 This variant is present in population databases and therefore is not absent from controls. In gnomAD v2.1 the total allele frequency is 0.00142% (4/282526), and in gnomAD v4.1 the total allele frequency is 0.00149% (24/1612526). Details ▾Hide ▴
Rule
PM2_Supporting requires absence from gnomAD.
Evidence considered
- gnomAD v2.1 total AF 1.4158e-05
- gnomAD v4.1 total AF 1.48835e-05
Sources
PM6 Available evidence does not support an assumed de novo occurrence. The published prenatal case showed paternal inheritance, which argues against PM6. Details ▾Hide ▴
Rule
PM6 uses the RASopathy de novo point system for assumed de novo occurrences.
Evidence considered
- Prenatal case with unaffected heterozygous father
- No assumed de novo report identified
Still missing
- No assumed de novo case lacking full parental confirmation was identified.
Sources
PP1 No segregation data were identified showing this variant cosegregates with disease in enough informative meioses to meet PP1. Details ▾Hide ▴
Rule
PP1 requires at least 3 informative meioses for supporting strength.
Evidence considered
- No qualifying cosegregation data found
Still missing
- No pedigree or segregation series with at least 3 informative meioses was identified.
Sources
PP3 Computational evidence does not meet the BRAF RASopathy PP3 threshold. REVEL is 0.318, which is below the PP3 cutoff of 0.7, and SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.01. Details ▾Hide ▴
Rule
PP3 for missense variants requires REVEL >=0.7; for splicing, the predicted outcome must match disease mechanism.
Evidence considered
- REVEL 0.318
- SpliceAI max delta 0.01
- BayesDel -0.174758
Sources
BA1 Population frequency is far below the BA1 threshold. The highest reviewed gnomAD total allele frequency is 0.00149%, which is below the BRAF RASopathy BA1 threshold of 0.05%. Details ▾Hide ▴
Rule
BA1 requires gnomAD filtering allele frequency >=0.05%.
Evidence considered
- gnomAD v4.1 total AF 0.00149%
- gnomAD v2.1 total AF 0.00142%
Sources
BS1 Population frequency is below the BS1 threshold. The highest reviewed gnomAD total allele frequency is 0.00149%, which is below the BRAF RASopathy BS1 threshold of 0.025%. Details ▾Hide ▴
Rule
BS1 requires gnomAD filtering allele frequency >=0.025%.
Evidence considered
- gnomAD v4.1 total AF 0.00149%
- gnomAD v2.1 total AF 0.00142%
Sources
BS4 No formal nonsegregation study was identified that meets the framework requirement for BS4. A single inherited occurrence from a reportedly unaffected parent does not by itself provide a sufficiently documented lack-of-segregation dataset for confident BS4 assignment. Details ▾Hide ▴
Rule
BS4 requires lack of segregation; the framework notes one informative meiosis can be sufficient when adequately documented.
Evidence considered
- Inherited occurrence from an unaffected parent reported
- No formal segregation dataset identified
Still missing
- A documented pedigree or segregation table demonstrating informative nonsegregation was not identified.
Sources
BP2 No evidence was identified that this variant occurred with an alternative pathogenic RASopathy variant in the same gene in a way that would support BP2. Details ▾Hide ▴
Rule
BP2 uses the RASopathy benign point system for alternative molecular causes in the same gene.
Evidence considered
- No same-gene alternative pathogenic variant identified
Still missing
- No qualifying same-gene alternative molecular cause was identified.
Sources
BP4 Computational evidence does not meet the benign missense threshold because REVEL is 0.318, which is above the BP4 cutoff of 0.3. SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.01, but this does not rescue BP4 for this missense variant under the reviewed rule. Details ▾Hide ▴
Rule
BP4 for missense variants requires REVEL <=0.3.
Evidence considered
- REVEL 0.318
- SpliceAI max delta 0.01
- BayesDel -0.174758
Sources
BP5 No alternative molecular explanation in a different gene, and no fully established non-RASopathy diagnosis explaining the reported findings, was identified from the reviewed evidence. Details ▾Hide ▴
Rule
BP5 uses the RASopathy benign point system for alternative molecular causes in a different gene or clearly inconsistent phenotypes explained by another cause.
Evidence considered
- No alternative pathogenic variant in a different gene identified in the reviewed cases
Still missing
- No qualifying different-gene molecular diagnosis was identified.
Sources
Not assessed · 3 · no assessment recorded
PS1 No reviewed source identified a previously established pathogenic variant producing the same amino acid change, so PS1 could not be confirmed from the available evidence. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic variant.
Evidence considered
- BRAF RASopathy PS1 rule reviewed
- RAF alignment workbook reviewed without codon-208 support recoverable from the available materials
Still missing
- A codon-level review showing whether another pathogenic nucleotide change produces p.Ile208Val was not identified.
Sources
cspec ↗vcep_raf_alignment
PM5 No reviewed source established a pathogenic missense change at this codon or an approved analogous RAF residue that would allow PM5 to be assigned with confidence. Details ▾Hide ▴
Rule
PM5_Moderate requires one pathogenic or likely pathogenic residue change at the same codon; PM5_Strong requires at least two different pathogenic or likely pathogenic residue changes at the same codon observed in at least five probands.
Evidence considered
- BRAF RASopathy PM5 rule reviewed
- RAF alignment workbook reviewed without codon-208 support recoverable from the available materials
Still missing
- A codon-specific lookup confirming whether another pathogenic missense change exists at BRAF codon 208 or the approved analogous RAF residue was not recoverable from the reviewed materials.
Sources
cspec ↗vcep_raf_alignment
PP2 The BRAF RASopathy specification uses a gnomAD missense Z-score threshold greater than 3.09 for PP2, but that gene-level value was not available in the reviewed materials. Details ▾Hide ▴
Rule
PP2 applies if missense Z-score is >3.09 in gnomAD.
Evidence considered
- BRAF RASopathy PP2 rule reviewed
Still missing
- The gnomAD missense Z-score for BRAF was not retrieved in the available evidence files.
Sources
Not applicable · 10· 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 marks PVS1 as not applicable for this variant context. Details ▾Hide ▴
Rule
PVS1 not applicable for this variant context.
Evidence considered
- Missense change p.Ile208Val
- Generic PVS1 scaffold does not apply
- BRAF VCEP marks PVS1 not applicable
Sources
cspec ↗pvs1_variant_assessment
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 does not apply. Details ▾Hide ▴
Rule
PM4 applies to protein length changes due to in-frame indels or stop-loss variants.
Evidence considered
- Missense change p.Ile208Val
Sources
PP4 N/APP4 is not applicable in this BRAF RASopathy framework because phenotype weighting is handled through PS4. Details ▾Hide ▴
Rule
Not applicable; see PS4.
Evidence considered
- BRAF RASopathy specification reviewed
Sources
PP5 N/APP5 is not used in this VCEP framework. Details ▾Hide ▴
Rule
Not for use as recommended by the ClinGen SVI VCEP Review Committee.
Evidence considered
- BRAF RASopathy specification reviewed
Sources
BS3 N/ABS3 is not applicable in this BRAF RASopathy framework. Details ▾Hide ▴
BP1 N/AThis is not a truncating or canonical splice variant, so BP1 does not apply under the BRAF RASopathy specification. Details ▾Hide ▴
Rule
BP1 is used here for truncating variants in genes with gain-of-function disease mechanism and no established loss-of-function correlation.
Evidence considered
- Missense change p.Ile208Val
Sources
BP3 N/ABP3 is not applicable in this BRAF RASopathy framework. Details ▾Hide ▴
BP6 N/ABP6 is not used in this VCEP framework. Details ▾Hide ▴
Rule
Not for use as recommended by the ClinGen SVI VCEP Review Committee.
Evidence considered
- BRAF RASopathy specification reviewed
Sources
BP7 N/AThis is not a synonymous, intronic, or noncoding variant, so BP7 does not apply. Details ▾Hide ▴
Rule
BP7 applies to synonymous or certain noncoding variants with no predicted splice impact.
Evidence considered
- Missense change p.Ile208Val
Sources
Identifiers
- Gene
- BRAF
- Transcript
- NM_001354609.1
- Coding (HGVS c.)
- NM_001354609.1:c.622A>G
- Protein (HGVS p.)
- NP_001341538.1:p.(Ile208Val)
- GRCh38
- chr7:140808049 T>C
- GRCh37
- chr7:140507849 T>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
—
Transcript span
—
Strand
—
Variants mapped
—
Source
UCSC ncbiRefSeqCurated
All variants in BRAF
—
Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
24 / 1,612,526 alleles
AF 1.49e-05 · 0 homozygotes · FAF 1.15e-05
gnomAD v2.1
4 / 282,526 alleles
AF 1.42e-05 · 0 homozygotes · FAF 7.02e-06
By genetic ancestry
gnomAD v4.1
AF 1.5e-05 · 24 / 1,612,526 alleles · 0 hom · FAF 1.1e-05
| African/African American2 / 74,860 | 2.7e-05 |
| European (non-Finnish)21 / 1,178,824 | 1.8e-05 |
| South Asian1 / 91,040 | 1.1e-05 |
0 alternate alleles recorded in 7 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish.
gnomAD v2.1
AF 1.4e-05 · 4 / 282,526 alleles · 0 hom · FAF 7e-06
| European (non-Finnish)4 / 128,934 | 3.1e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.48835e-05; MAF= 0.00149%, 24/1612526 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 2.67165e-05; MAF= 0.00267%, 2/74860 alleles, homozygotes = 0); grpmax FAF= 1.145e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.4158e-05; MAF= 0.00142%, 4/282526 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.10236e-05; MAF= 0.00310%, 4/128934 alleles, homozygotes = 0); grpmax FAF= 7.02e-06.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 Computational evidence does not meet the BRAF RASopathy PP3 threshold. REVEL is 0.318, which is below the PP3 cutoff of 0.7, and SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.01. Details ▾Hide ▴
Rule
PP3 for missense variants requires REVEL >=0.7; for splicing, the predicted outcome must match disease mechanism.
Evidence considered
- REVEL 0.318
- SpliceAI max delta 0.01
- BayesDel -0.174758
Sources
BP4 Computational evidence does not meet the benign missense threshold because REVEL is 0.318, which is above the BP4 cutoff of 0.3. SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.01, but this does not rescue BP4 for this missense variant under the reviewed rule. Details ▾Hide ▴
Rule
BP4 for missense variants requires REVEL <=0.3.
Evidence considered
- REVEL 0.318
- SpliceAI max delta 0.01
- BayesDel -0.174758
Sources
BP7 N/AThis is not a synonymous, intronic, or noncoding variant, so BP7 does not apply. Details ▾Hide ▴
Rule
BP7 applies to synonymous or certain noncoding variants with no predicted splice impact.
Evidence considered
- Missense change p.Ile208Val
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.318. BayesDel score = -0.174758.
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
24 / 1,612,526 recorded alleles
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/178963/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/7-140507849-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr7-140808049-T-C?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001354609.1%3Ac.6…
- OncoKB ↗www.oncokb.org/gene/BRAF/I208V
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRAF+c.622A%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= 1.48835e-05; MAF= 0.00149%, 24/1612526 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 2.67165e-05; MAF= 0.00267%, 2/74860 alleles, homozygotes = 0); grpmax FAF= 1.145e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.4158e-05; MAF= 0.00142%, 4/282526 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.10236e-05; MAF= 0.00310%, 4/128934 alleles, homozygotes = 0); grpmax FAF= 7.02e-06.
ClinVar
This variant has been reported in ClinVar as Likely benign (4 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as Uncertain significance by ClinGen RASopathy Variant Curation Expert Panel (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.318. BayesDel score = -0.174758.
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.