The PIK3CA c.2740G>A (p.Gly914Arg) variant has been observed in somatic cancers in COSMIC (9 occurrences) and has been reported in ClinVar with an expert panel pathogenic classification.1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population controls and meeting the Brain Malformations VCEP PM2_Supporting requirement.2 In a published functional study of megalencephaly-associated PI3K-pathway variants, mutant lymphoblastoid cell lines showed increased PIP3 and increased downstream S6 and 4E-BP1 phosphorylation, consistent with gain-of-function pathway activation, although an exact p.Gly914Arg-specific validated assay was not identified.3 REVEL was 0.871, BayesDel was 0.382681, and SpliceAI predicted no significant splice impact with a maximum delta score of 0.13; however, this VCEP does not apply PP3 to gain-of-function missense variants.4
PIK3CA
Final classification
VUS
PIK3CA c.2740G>A · p.Gly914Arg
PIK3CA
The PIK3CA c.2740G>A (p.Gly914Arg) variant has been observed in somatic cancers in COSMIC (9 occurrences) and has been reported in ClinVar with an expert panel pathogenic classification.
Brain Malformations Specification Tavtigian point framework v1.1.0 point-based framework: PS2 moderate (+2) + PM1 supporting (+1) + PP5 supporting (+1) + PM2 supporting (+1) = 5 points, which maps to VUS.
Classification rationale
PS2PM1PP5PM2
VUS
PIK3CA c.2740G>A
PS2 + PM1 + PP5 + PM2
→
VUS
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 (13 clinical laboratories) and as Likely pathogenic (3 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 = 0.13). REVEL score = 0.871. BayesDel score = 0.382681.
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely 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; COSV55930478, n = 9 times).
Hotspots
This variant lies in a statistically significant hotspot.
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.
De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a sp
Found
Structured finding pending for this record — see source link.
Applied to
→PS2 supports · met
Sources & reference links