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.1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports rarity in population reference datasets.2 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.3 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 PP3.4
PIK3CA
Final classification
VUS
PIK3CA c.1624G>A · p.Glu542Lys
PIK3CA
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.
Brain Malformations Specification Tavtigian point framework v1.1.0 point-based framework: PP5 supporting (+1) + PM5 moderate (+2) + PM2 supporting (+1) + PS3 supporting (+1) = 5 points, which maps to VUS.
Classification rationale
PP5PM5PM2PS3
VUS
PIK3CA c.1624G>A
PP5 + PM5 + PM2 + PS3
→
VUS
4
spliceai ↗revelbayesdelcspec ↗
Gene diagram
· NM_006218.2 · variants mapped to exon structure
PIK3CA
NM_006218.2
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
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
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
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.439. BayesDel score = 0.232897.
Functional
Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Oncogenic.
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; COSV55873227, n = 1958 times).
Hotspots
This variant lies in a statistically significant hotspot.
Literature · how each cited paper was used
3papers 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:16432179
Found
Structured finding pending for this record — see source link.
Applied to
→PS3 supports · met
PMID PMID:17376864
Found
Structured finding pending for this record — see source link.
Applied to
→PS3 supports · met
PMID PMID:26627007
Found
Structured finding pending for this record — see source link.
Applied to
→PS3 supports · met
Sources & reference links