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LYFE SCIENCES
Project: HERA
NM_001354609.1:c.1406G>A
p.Gly469Glu  ·  BRAF
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Classification rationale
1

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.

oncokb ↗ clinvar ↗
2

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.

gnomad_v2 ↗ gnomad_v4 ↗ gnomad_canada ↗
3

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.

PMID:18794803 ↗
4

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).

spliceai ↗ cspec ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1This 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).
gnomAD v4.1This 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).
gnomAD CanadaAbsent from gnomAD-Canada v1.0.
gnomAD v2 ↗ gnomAD v4 ↗ gnomAD 🇨🇦 ↗
ClinVar evidence
02
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 ↗
Functional evidence
03
Functional
OncoKB: Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Oncogenic.
OncoKB ↗
In silico evidence
04
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 ↗
COSMIC evidence
05
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV56065622, n = 36 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant lies in a statistically significant hotspot.
ResidueG469
Hotspots ↗