Starting

Initialising…

BRAF

Final classification

Likely Pathogenic

BRAF c.741T>G · p.Phe247Leu

BRAF

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.

Gene

BRAF

Transcript

NM_001354609.1

HGVS · transcript:coding

NM_001354609.1:c.741T>G

Consequence

N/A

GRCh38

chr7:140801531 A>C

GRCh37

chr7:140501331 A>C

Basis ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRAF Version 2.3.0 v2.3.0 criteria-combination framework: matched Rule14 (2 Pathogenic.Moderate + Pathogenic.Supporting >=2) with applied criteria: PM1 moderate, PM2 supporting, PM5 moderate, PP3 supporting, PP5 supporting; maps to Likely Pathogenic. ▾

ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRAF Version 2.3.0 v2.3.0 criteria-combination framework: matched Rule14 (2 Pathogenic.Moderate + Pathogenic.Supporting >=2) with applied criteria: PM1 moderate, PM2 supporting, PM5 moderate, PP3 supporting, PP5 supporting; maps to Likely Pathogenic.

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 ↗

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

BRAF NM_001354609.1

Fetching transcript structure from UCSC…

Applied criteria · 5 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

Benign evidence

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

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