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LYFE SCIENCES
Project: HERA
NM_001354609.1:c.622A>G
p.Ile208Val  ·  BRAF
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Classification rationale
1

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.

clinvar ↗ PMID:29945942 ↗
2

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.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

No approved variant-specific functional study was identified for p.Ile208Val in the reviewed RASopathy functional-study materials.

cspec ↗
4

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.

spliceai ↗ cspec ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
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Gaps remaining
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Rule
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Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1This 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.
gnomAD v4.1This 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 ↗ gnomAD v4 ↗
ClinVar evidence
02
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).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: 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.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.318. BayesDel score = -0.174758.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueI208
Hotspots ↗