Starting

Initialising…

BRAF

Final classification

VUS

BRAF c.1787G>T · p.Gly596Val

BRAF

The BRAF c.1787G>T (p.Gly596Val) variant has been observed in somatic cancers in COSMIC and has been reported in ClinVar as Pathogenic with expert-panel review.

Gene

BRAF

Transcript

NM_001354609.1

HGVS · transcript:coding

NM_001354609.1:c.1787G>T

Consequence

N/A

GRCh38

chr7:140753348 C>A

GRCh37

chr7:140453148 C>A

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 was evaluated deterministically with applied criteria: PS3 supporting, PM1 moderate, PM2 supporting, PP3 supporting, PP5 supporting; no rule matched the adjudicated criteria. ▾

ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRAF Version 2.3.0 v2.3.0 criteria-combination framework was evaluated deterministically with applied criteria: PS3 supporting, PM1 moderate, PM2 supporting, PP3 supporting, PP5 supporting; no rule matched the adjudicated criteria.

Classification rationale

PS3PM1PM2PP3PP5 VUS

BRAF c.1787G>T

The BRAF c.1787G>T (p.Gly596Val) variant has been observed in somatic cancers in COSMIC and has been reported in ClinVar as Pathogenic with expert-panel review.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports rarity in population reference datasets.² In a published functional study, BRAF p.Gly596Val caused abnormal zebrafish developmental phenotypes and showed downstream ERK activation, consistent with dysregulated MAPK signaling.³ Computational evidence supports a deleterious missense effect, with REVEL 0.989 above the BRAF PP3 threshold of 0.7, BayesDel 0.588239, and SpliceAI predicting no significant splice effect with a maximal delta score of 0.07.⁴

PS3 + PM1 + PM2 + PP3 + PP5 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 PMID:19376813 ↗vcep_svi_rasopathy_vcep_v2_approved_functional_studies

4 revelbayesdelspliceai ↗cspec ↗

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

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

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07). REVEL score = 0.989. BayesDel score = 0.588239.

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 lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV99951808, n = 1 times).

Hotspots

This variant lies in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

1papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.

PMID PMID:19376813

PMID PMID:19376813 ↗

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