Classification rationale

PS3PM1PM2PP3PP5 VUS

BRAF c.1406G>A

The BRAF c.1406G>A (p.Gly469Glu) variant has been observed in somatic cancers and has been reported in ClinVar with an expert panel pathogenic classification.¹ This variant is absent from gnomAD v2.1 (0/251420 alleles), gnomAD v4.1 (0/1614020 alleles), and gnomAD-Canada, which supports rarity in population databases.² In the RASopathy VCEP approved functional-study resource, p.Gly469Glu is listed as a pathogenic BRAF control in both MEK activation and ERK activation assays, and a published functional study showed constitutive ERK phosphorylation with low MEK phosphorylation, consistent with abnormal pathway activation.³ Computational data support a damaging missense effect, with REVEL 0.949 above the PP3 threshold, BayesDel 0.454064, and no predicted splice disruption by SpliceAI (max delta score 0.00).⁴

PS3 + PM1 + PM2 + PP3 + PP5 → VUS

1 oncokb ↗clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

3 vcep_svi_rasopathy_vcep_v2_approved_functional_studiesPMID:18794803 ↗

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

PS

PM

PP

Benign evidence

BA

BS

BP

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1614020 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/75050 alleles, homozygotes = 0).

v2.1

This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/251420 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16256 alleles, homozygotes = 0).

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / 1,614,020
0 hom

Not observed in any ancestry group.

+ 10 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))

gnomAD v2.1

Absent · 0 / 251,420
0 hom

Not observed in any ancestry group.

+ 8 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Pathogenic (14 clinical laboratories) and as Pathogenic by ClinGen RASopathy Variant Curation Expert Panel (expert panel). (ClinVarID = 13974)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.949. BayesDel score = 0.454064.

SpliceAI ↗

Functional Oncogenic

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: 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; COSV56065622, n = 36 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. 6 further PMIDs triaged but not cited — see Sources & References.

PMID PMID:18794803

PMID PMID:18794803 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→PS3 supports · met

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 6 PMIDs not cited in assessment

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

16439621 ↗ Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome. ONCOKB

18794803 ↗ CRAF inhibition induces apoptosis in melanoma cells with non-V600E BRAF mutations. ONCOKB

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

15150094 ↗ Different effects of point mutations within the B-Raf glycine-rich loop in colorectal tumors on mitogen-activated protein/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase and nuclear factor kappaB pathway and cellular transformation. ONCOKB

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