Starting

Initialising…

BRAF

Final classification

VUS

BRAF c.730A>C · p.Thr244Pro

BRAF

The BRAF c.730A>C (p.Thr244Pro) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as Pathogenic, including an expert panel Pathogenic classification.

Gene

BRAF

Transcript

NM_001354609.1

HGVS · transcript:coding

NM_001354609.1:c.730A>C

Consequence

N/A

GRCh38

chr7:140801542 T>G

GRCh37

chr7:140501342 T>G

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: 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: PM1 moderate, PM2 supporting, PP3 supporting, PP5 supporting; no rule matched the adjudicated criteria.

Classification rationale

PM1PM2PP3PP5 VUS

BRAF c.730A>C

The BRAF c.730A>C (p.Thr244Pro) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as Pathogenic, including an expert panel Pathogenic classification.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population controls.² This missense change affects BRAF exon 6, a region specified by the RASopathy VCEP for PM1, and computational evidence supports a deleterious missense effect with REVEL 0.855, BayesDel 0.418359, and no major predicted splice effect by SpliceAI (maximum delta score 0.09).³

PM1 + PM2 + PP3 + PP5 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 cspec ↗revelbayesdelspliceai ↗

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

BRAF NM_001354609.1

Fetching transcript structure from UCSC…

Applied criteria · 4 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 (4 clinical laboratories) 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 = 0.09). REVEL score = 0.855. BayesDel score = 0.418359.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BRAF, an intracellular kinase, is frequently mutated in melanoma, thyroid and lung cancers among others.

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