Classification rationale

PM1PM2PM5PP3PP5 Likely Pathogenic

BRAF c.741T>G

The BRAF c.741T>G (p.Phe247Leu) variant has been observed in somatic cancer once in COSMIC and has been reported in ClinVar with an expert-panel Pathogenic classification.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population databases.² Within the BRAF RASopathy framework, this missense change lies in exon 6, a specified critical functional domain, and other expert-panel reviewed missense substitutions at the same codon, p.Phe247Val and p.Phe247Ser, have been classified as likely pathogenic.³ Computational evidence supports a deleterious missense effect, with REVEL 0.816 exceeding the PP3 threshold of 0.7, while SpliceAI predicts no significant splice impact with a maximum delta score of 0.08.⁴

PM1 + PM2 + PM5 + PP3 + PP5 → Likely Pathogenic

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 cspec ↗clinvar ↗

4 revelspliceai ↗bayesdelcspec ↗

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 located in BRAF exon 6, and the BRAF RASopathy specification lists exon 6 as a critical and well-established functional domain for PM1 application.

Variant normalization places c.741T>G / p.(Phe247Leu) in exon 6.The BRAF RASopathy specification states that PM1 is applicable to 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 threshold of absence from controls.

gnomAD v2.1: absent.gnomAD v4.1: absent.The BRAF RASopathy specification applies PM2 at supporting strength when the variant is absent from gnomAD.

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

PM5 moderate review Pathogenic

Other missense changes at the same codon have been reported in ClinVar with expert-panel review, including p.(Phe247Val) and p.(Phe247Ser), both classified as likely pathogenic. This supports PM5 at moderate strength for a different missense change at the same residue.

ClinVar documents BRAF p.(Phe247Val) as likely pathogenic with expert-panel review.ClinVar documents BRAF p.(Phe247Ser) as likely pathogenic with expert-panel review.The BRAF RASopathy specification allows PM5 moderate for one likely pathogenic/pathogenic residue change at the same codon and strong for two different such changes observed in at least 5 probands.

cspec ↗clinvar ↗

PP3 supporting review Pathogenic

Computational evidence supports a deleterious missense effect. REVEL is 0.816, which is above the BRAF RASopathy PP3 threshold of 0.7, while SpliceAI predicts no significant splice impact with a maximum delta score of 0.08, supporting a protein-level rather than splice-driven effect.

REVEL score: 0.816.SpliceAI max delta score: 0.08.BayesDel score: 0.227743.

cspec ↗spliceai ↗

PP5 supporting review Pathogenic

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

The BRAF RASopathy specification lists PP5 as not applicable.ClinVar expert panel classification

cspec ↗clinvar ↗

Assessed · not applied · 4 not met · 10 not assessed

Pathogenic

PS1 No previously established pathogenic variant producing the same amino acid change, p.(Phe247Leu), by a different nucleotide change was identified in the reviewed sources, so PS1 is not met.

PS2 No confirmed de novo occurrence with confirmed maternity and paternity was identified in the reviewed evidence, so PS2 cannot be applied at this time.

PS3 Approved functional assay frameworks were identified for BRAF, but no directly reviewed variant-specific assay result for p.(Phe247Leu) was available here, so PS3 was not applied.

PS4 The variant is classified by an expert panel in ClinVar, but the reviewed evidence did not provide the case counts or point-based affected-individual data needed to score PS4 within the BRAF RASopathy framework.

PM6 No assumed de novo occurrence without confirmed parentage was identified in the reviewed evidence, so PM6 was not applied.

PP1 No segregation data were identified for this variant, so PP1 cannot be applied.

PP2 This is a missense variant in BRAF, but the reviewed evidence did not provide the gene-level missense constraint value needed to determine whether the missense z score exceeds the BRAF RASopathy PP2 threshold.

Benign

BA1 This variant is absent from gnomAD v2.1 and v4.1, so it does not meet the BA1 population threshold of filtering allele frequency at or above 0.05%.

BS1 This variant is absent from gnomAD v2.1 and v4.1, so it does not meet the BS1 population threshold of filtering allele frequency at or above 0.025%.

BS2 No evidence was identified showing this variant in unaffected individuals in numbers sufficient for BS2 scoring.

BS4 No lack-of-segregation evidence was identified for this variant, so BS4 cannot be applied.

BP2 No evidence was identified for an alternative molecular explanation in cis or trans that would support BP2 scoring.

BP4 Available computational evidence does not support BP4 for a benign missense effect.

BP5 No evidence was identified for a fully explanatory alternative molecular diagnosis or a phenotype inconsistent with a RASopathy that would support BP5 scoring.

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

Research & evidence

Population frequency · supports pathogenic

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 (3 clinical laboratories) and as Likely pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen RASopathy Variant Curation Expert Panel (expert panel). (ClinVarID = 55793)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.08). REVEL score = 0.816. BayesDel score = 0.227743.

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 previously been reported in somatic cancers (COSMIC; COSV56165267, n = 1 times).

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

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