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LYFE SCIENCES
Project: HERA
NM_001354609.1:c.1024A>G
p.Ile342Val  ·  BRAF
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Classification rationale
1

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.

clinvar ↗
2

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.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

No variant-specific result from an approved RASopathy VCEP functional assay was identified for p.Ile342Val, so functional evidence was insufficient to apply PS3.

cspec ↗
4

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.

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
  • —
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= 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.
gnomAD v4.1This 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 ↗ gnomAD v4 ↗
ClinVar evidence
02
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)
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 possible splice impact for this variant (max delta score = 0.58). REVEL score = 0.269. BayesDel score = -0.184306.
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.
ResidueI342
Hotspots ↗