Classification rationale

PM1PM2PP2PP3PP5 VUS

BRAF c.739T>C

The BRAF c.739T>C (p.Phe247Leu) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as pathogenic, including by the ClinGen RASopathy Variant Curation Expert Panel.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, consistent with the BRAF RASopathy PM2_Supporting requirement for absence from population controls.² This missense change lies in BRAF exon 6, a region specifically designated by the BRAF RASopathy specification as eligible for PM1.³ Computational evidence supports a deleterious effect, with REVEL 0.902 above the BRAF RASopathy PP3 threshold of 0.7, BayesDel 0.278133, and SpliceAI showing no meaningful splice impact with a maximum delta score of 0.10.⁴

PM1 + PM2 + PP2 + PP3 + PP5 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 cspec ↗

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 · 5 applied · 14 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 · 5

Strength Supporting Moderate Strong Very strong

PM1 moderate review Pathogenic

This missense variant is in BRAF exon 6, and the BRAF RASopathy specification lists exon 6 as a critical, well-established region eligible for PM1.

Variant localizes to exon 6BRAF RASopathy PM1 rule explicitly includes exon 6

cspec ↗

PM2 supporting review Pathogenic

This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, which meets the BRAF RASopathy PM2 requirement of absence from population controls.

Absent from gnomAD v2.1Absent from gnomAD v4.1

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

PP2 supporting review Pathogenic

This is a missense variant in BRAF, a gene with missense-mediated RASopathy disease, and the gene-level gnomAD missense z score is 3.72, which is above the BRAF RASopathy PP2 threshold of 3.09.

BRAF RASopathy PP2 threshold is missense z score >3.09Live gnomAD gene constraint query showed missense z score 3.72

cspec ↗gnomad_v4 ↗

PP3 supporting review Pathogenic

Computational evidence supports a deleterious missense effect: REVEL is 0.902, which is above the BRAF RASopathy PP3 threshold of 0.7, while SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.10. BayesDel is also positive at 0.278133.

REVEL 0.902SpliceAI max delta 0.10BayesDel 0.278133

cspec ↗spliceai ↗

PP5 supporting review Pathogenic

Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Pathogenic.

PP5 marked not applicable in BRAF criteriaClinVar expert panel classification

cspec ↗clinvar ↗

Assessed · not applied · 3 not met · 11 not assessed

Pathogenic

PS1 No verified evidence was identified showing the same amino acid change from a different nucleotide substitution, or an established analogous RAF1/BRAF residue match that satisfies the BRAF RASopathy PS1 rule.

PS2 Published evidence suggesting possible de novo occurrence was flagged for follow-up, but no directly verified proband-level parental testing details were available to assign de novo points under the BRAF RASopathy framework.

PS3 Review of the RASopathy VCEP approved functional study materials did not confirm this exact variant in a qualifying approved assay, so pathogenic functional evidence was not applied.

PS4 The variant is reported in ClinVar, but a deduplicated count of unrelated affected individuals and the corresponding RASopathy point total were not directly verified from the available materials, so PS4 was not assigned.

PM5 The BRAF framework uses classic same-residue PM5 logic, but no verified qualifying pathogenic or likely pathogenic missense comparator at codon 247 was confirmed from the available materials.

PM6 Possible de novo literature sources were identified, but no directly verified report was available to determine whether reduced de novo points should be assigned under PM6.

PP1 No segregation data were identified showing this variant co-segregating with disease in informative meioses.

Benign

BA1 This variant is absent from gnomAD v2.1 and v4.1 and therefore is below the BRAF RASopathy BA1 threshold of 0.05% filtering allele frequency.

BS1 This variant is absent from gnomAD v2.1 and v4.1 and therefore is below the BRAF RASopathy BS1 threshold of 0.025% filtering allele frequency.

BS2 No evidence was identified showing this variant in unaffected individuals sufficient to assign benign observation points.

BS4 No lack-of-segregation evidence was identified for this variant in an informative family.

BP2 No co-occurrence or phase data were identified showing this variant with an alternative molecular cause of disease in the same gene.

BP4 Although SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.10, the missense REVEL score is 0.902, which is well above the BRAF RASopathy BP4 threshold of 0.3, so benign computational evidence is not supported.

BP5 No alternative molecular explanation for the phenotype was identified that would support benign points under BP5.

N/A · 9 PVS1 · PM3 · PM4 · PP4 · BS3 · BP1 · BP3 · BP6 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Pathogenic (4 clinical laboratories) and as Likely pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen RASopathy Variant Curation Expert Panel (expert panel). (ClinVarID = 180784)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10). REVEL score = 0.902. BayesDel score = 0.278133.

SpliceAI ↗

Functional Likely Oncogenic

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.

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 · 9 PMIDs not cited in assessment

28512244 ↗ Engineering and Functional Characterization of Fusion Genes Identifies Novel Oncogenic Drivers of Cancer. ONCOKB

29533785 ↗ Systematic Functional Annotation of Somatic Mutations in Cancer. ONCOKB

31515458 ↗ Response to Anti-EGFR Therapy in Patients with BRAF non-V600-Mutant Metastatic Colorectal Cancer. ONCOKB

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

20301303 ↗ Noonan Syndrome. CLINVAR

20301365 ↗ PMID:20301365 CLINVAR

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

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