Classification rationale

VUS

BRAF c.1024A>G

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

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 vcep_svi_rasopathy_vcep_v2_approved_functional_studiescspec ↗

4 revelbayesdelspliceai ↗cspec ↗

Gene diagram · NM_001354609.1 · variants mapped to exon structure

BRAF NM_001354609.1

Fetching transcript structure from UCSC…

Applied criteria · 0 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

PS

PM

PP

Benign evidence

BA

BS

BP

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

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%

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%

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))

gnomAD v4 ↗ gnomAD v2 ↗

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 ↗

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.58). REVEL score = 0.269. BayesDel score = -0.184306.

SpliceAI ↗

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.

OncoKB ↗

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.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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

20301303 ↗ Noonan Syndrome. CLINVAR

20301365 ↗ Cardiofaciocutaneous Syndrome. CLINVAR

20301390 ↗ PMID:20301390 CLINVAR

20301557 ↗ Noonan Syndrome with Multiple Lentigines. CLINVAR

20876176 ↗ Noonan syndrome: clinical features, diagnosis, and management guidelines. 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