Starting

Initialising…

BRAF

Final classification

Likely Pathogenic

BRAF c.1799T>G · p.Val600Gly

BRAF

Gene

BRAF

Transcript

NM_001354609.1

HGVS · transcript:coding

NM_001354609.1:c.1799T>G

Consequence

N/A

GRCh38

chr7:140753336 A>C

GRCh37

chr7:140453136 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: PS3 supporting, 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: PS3 supporting, PM1 moderate, PM2 supporting, PM5 moderate, PP3 supporting, PP5 supporting; maps to Likely Pathogenic.

Classification rationale

PS3PM1PM2PM5PP3PP5 Likely Pathogenic

BRAF c.1799T>G

The BRAF c.1799T>G (p.Val600Gly, p.V600G) variant has been observed in somatic cancers, including 27 occurrences in COSMIC, and has been reported in ClinVar with a Pathogenic expert-panel classification from the ClinGen RASopathy Variant Curation Expert Panel.¹ This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, supporting rarity in population reference datasets.² In a published functional study, p.Val600Gly increased ERK and ELK phosphorylation relative to wild type, consistent with an activating effect; the BRAF RASopathy functional-study framework supports PS3 at supporting strength when one approved assay is available.³ Computational evidence supports a damaging missense effect, with REVEL 0.925 above the BRAF RASopathy PP3 threshold of 0.7, BayesDel 0.357299, and SpliceAI showing no major splice effect with a maximum delta score of 0.11.⁴

PS3 + PM1 + PM2 + PM5 + PP3 + PP5 → Likely Pathogenic

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 PMID:20735442 ↗cspec ↗vcep_svi_rasopathy_vcep_v2_approved_functional_studies

4 cspec ↗revelbayesdelspliceai ↗

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

BRAF NM_001354609.1

Fetching transcript structure from UCSC…

Applied criteria · 6 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 Uncertain significance (1 clinical laboratory) and as Pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen RASopathy Variant Curation Expert Panel (expert panel). (ClinVarID = 40389)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.11). REVEL score = 0.925. BayesDel score = 0.357299.

SpliceAI ↗

Functional Likely Oncogenic

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

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV56080151, n = 27 times).

Hotspots

This variant lies in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

2papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 8 further PMIDs triaged but not cited — see Sources & References.

PMID PMID:15035987

PMID PMID:15035987 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→PM1 supports · met

PMID PMID:20735442

PMID PMID:20735442 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→PS3 supports · met

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 8 PMIDs not cited in assessment

20735442 ↗ Germline mutation in BRAF codon 600 is compatible with human development: de novo p.V600G mutation identified in a patient with CFC syndrome. ONCOKB

12068308 ↗ Mutations of the BRAF gene in human cancer. ONCOKB

15035987 ↗ Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. ONCOKB

16273091 ↗ BRAF mutation predicts sensitivity to MEK inhibition. ONCOKB

26287849 ↗ Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations. ONCOKB

28783719 ↗ Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS. ONCOKB

31275557 ↗ Pan-cancer repository of validated natural and cryptic mRNA splicing mutations. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR