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.1 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.2 No approved variant-specific functional study was identified for p.Ile208Val in the reviewed RASopathy functional-study materials.3 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 -0.174758.4
Final classification
VUS
BS2
BRAF
c.622A>G
p.Ile208Val
This variant
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.
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.
Classification rationale
BS2
VUS
BRAF c.622A>G
BS2
→
VUS
3
vcep_svi_rasopathy_vcep_v2_approved_functional_studiescspec ↗
4
revelspliceai ↗bayesdelcspec ↗
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.
Gene diagram
· NM_001354609.1 · variants mapped to exon structure
BRAF
NM_001354609.1
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 17 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
BS2
supporting
review
Benign
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.
Unaffected heterozygous fatherAt least three phenotyped individuals without a RASopathy reported in the publication
Assessed · not applied
· 14 not met · 3 not assessed
Pathogenic
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.
PS2
Available evidence does not support a confirmed de novo occurrence.
PS3
No approved variant-specific functional assay result was identified for p.Ile208Val.
PS4
Available evidence does not show enrichment of this variant in affected individuals.
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).
PM2
This variant is present in population databases and therefore is not absent from controls.
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.
PM6
Available evidence does not support an assumed de novo occurrence.
PP1
No segregation data were identified showing this variant cosegregates with disease in enough informative meioses to meet PP1.
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.
PP3
Computational evidence does not meet the BRAF RASopathy PP3 threshold.
Benign
BA1
Population frequency is far below the BA1 threshold.
BS1
Population frequency is below the BS1 threshold.
BS4
No formal nonsegregation study was identified that meets the framework requirement for BS4.
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.
BP4
Computational evidence does not meet the benign missense threshold because REVEL is 0.318, which is above the BP4 cutoff of 0.3.
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.
N/A · 10
PVS1 · PM3 · PM4 · PP4 · PP5 · BS3 · BP1 · BP3 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
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.
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.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0015%
· 24 / 1,612,526
0 hom · FAF 0.0011%
0 hom · FAF 0.0011%
African/African American 2 / 74,860 |
0.0027% |
European (non-Finnish) 21 / 1,178,824 |
0.0018% |
South Asian 1 / 91,040 |
0.0011% |
+ 7 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish)
gnomAD v2.1
0.0014%
· 4 / 282,526
0 hom · FAF 0.0007%
0 hom · FAF 0.0007%
European (non-Finnish) 4 / 128,934 |
0.0031% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
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
Unknown Oncogenic Effect
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.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · how each cited paper was used
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
Reclassification of the BRAF p.Ile208Val variant by case-level data sharing.
Found
Structured finding pending for this record — see source link.
Applied to
→BS2
supporting
Sources & reference links