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LYFE SCIENCES
Project: HERA
NM_006218.2:c.1624G>A
p.Glu542Lys  ·  PIK3CA
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Classification rationale
1

The PIK3CA c.1624G>A (p.Glu542Lys) variant has been observed in somatic cancers in COSMIC (COSV55873227, n=1958) and has been reported in ClinVar with an expert panel pathogenic classification for brain malformation-related disease.

clinvar ↗
2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports rarity in population reference datasets.

gnomad_v2 ↗ gnomad_v4 ↗
3

In published functional studies, PIK3CA E542K increased oncogenic activity, activated downstream AKT/TOR signaling, and promoted in vivo tumor formation relative to wild type, consistent with a gain-of-function effect.

PMID:16432179 ↗ PMID:17376864 ↗ PMID:26627007 ↗
4

Computational data show no predicted splice effect by SpliceAI (max delta score 0.00), with REVEL 0.439 and BayesDel 0.232897; under this gain-of-function VCEP these in silico results were not used to apply PP3.

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
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Pathogenic (9 clinical laboratories) and as Likely pathogenic (2 clinical laboratories) and as Pathogenic by ClinGen Brain Malformations Variant Curation Expert Panel (expert panel).
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 = 0.439. BayesDel score = 0.232897.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55873227, n = 1958 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant lies in a statistically significant hotspot.
ResidueE542
Hotspots ↗