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.1 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.2 No variant-specific result from an approved RASopathy VCEP functional assay was identified for p.Ile342Val, so functional evidence was insufficient to apply PS3.3 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.4
Final classification
VUS
BRAF
c.1024A>G
p.Ile342Val
This variant
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.
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.
Classification rationale
VUS
BRAF c.1024A>G
3
vcep_svi_rasopathy_vcep_v2_approved_functional_studiescspec ↗
4
revelbayesdelspliceai ↗cspec ↗
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 · 0 applied · 18 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 · 0
No criteria were applied for this variant.
Assessed · not applied
· 8 not met · 10 not assessed
Pathogenic
PS1
No previously established pathogenic variant causing the same amino acid change was identified in the available evidence, so PS1 is not met.
PS2
No confirmed de novo occurrence with sufficient parental testing and phenotype detail was identified for this variant, so PS2 was not assessed.
PS3
No variant-specific result from an approved functional assay was identified for p.(Ile342Val), so PS3 was not assessed.
PS4
No exact-variant case series or case-count evidence showing enrichment in affected individuals was identified, so PS4 was not assessed.
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).
PM2
This variant is present in population databases and therefore is not absent from controls.
PM5
No different pathogenic or likely pathogenic missense change at the same residue was identified in the available evidence, so PM5 is not met.
PM6
No apparently de novo occurrence without confirmed parentage was identified for this variant, so PM6 was not assessed.
PP1
No segregation data or informative meioses were identified for this variant, so PP1 was not assessed.
PP2
PP2 was not assessed because a BRAF missense constraint value meeting the framework threshold was not identified in the reviewed evidence.
PP3
Available computational evidence does not meet the BRAF RASopathy PP3 rule.
Benign
BA1
The population frequency is below the BRAF RASopathy BA1 threshold.
BS1
The population frequency is below the BRAF RASopathy BS1 threshold.
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.
BS4
No family data showing lack of segregation were identified for this variant, so BS4 was not assessed.
BP2
No phase data or observation with another pathogenic variant were identified, so BP2 was not assessed.
BP4
Computational evidence is mixed and does not support applying BP4.
BP5
No alternate molecular explanation or points-based BP5 evidence was identified for this variant, so BP5 was not assessed.
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= 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.
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.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0057%
· 92 / 1,613,958
0 hom · FAF 0.0052%
0 hom · FAF 0.0052%
Remaining individuals 6 / 62,502 |
0.0096% |
African/African American 7 / 74,956 |
0.0093% |
European (non-Finnish) 75 / 1,179,980 |
0.0064% |
Admixed American 2 / 60,010 |
0.0033% |
East Asian 1 / 44,874 |
0.0022% |
South Asian 1 / 91,068 |
0.0011% |
+ 4 not observed (European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish)
gnomAD v2.1
0.0039%
· 11 / 282,822
0 hom · FAF 0.0017%
0 hom · FAF 0.0017%
Remaining individuals 1 / 7,226 |
0.014% |
Admixed American 2 / 35,438 |
0.0056% |
European (non-Finnish) 6 / 129,154 |
0.0046% |
African/African American 1 / 24,958 |
0.004% |
South Asian 1 / 30,616 |
0.0033% |
+ 3 not observed (Ashkenazi Jewish, East Asian, European (Finnish))
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
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.
Sources & reference links
Triaged references · 10 PMIDs not cited in assessment
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.
CLINVAR
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.
CLINVAR
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.
CLINVAR
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).
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR