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
Final classification
VUS
PS2PM1PP5PM2
PIK3CA
c.2740G>A
p.Gly914Arg
This variant
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
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_006218.2 · variants mapped to exon structure
PIK3CA
NM_006218.2
Fetching transcript structure from UCSC…
Applied criteria · 4 applied · 11 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 4
Strength
Supporting
Moderate
Strong
Very strong
PS2
moderate
review
Pathogenic
This variant was reported as de novo in multiple affected individuals with MCAP, including parent-proband trio analysis in the original megalencephaly cohort, which supports PS2_Moderate. The stronger PS2 level was not applied because affected-tissue versus other-tissue allele-fraction data required for PS2_Strong were not established in the reviewed evidence.
PMID 22729224 lists p.Gly914Arg as de novo in multiple affected individualsVCEP PS2_Moderate requires criterion 1 or criterion 2 when parents are unavailable
PM1
supporting
review
Pathogenic
Residue Gly914 lies within the PIK3CA kinase-domain interval 797-1068 listed in Table 4 of the Brain Malformations VCEP specification, so PM1 is met at Supporting strength under the gene-specific domain rule.
PIK3CA p.Gly914ArgTable 4 approved kinase-domain interval 797-1068
PM2
supporting
review
Pathogenic
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the VCEP population threshold and supports PM2 at Supporting strength.
gnomAD v2.1 absentgnomAD v4.1 absentVCEP PM2 is Supporting with one person maximum
Assessed · not applied
· 4 not met · 7 not assessed
Pathogenic
PS1
No previously established pathogenic alternate nucleotide change producing the same p.Gly914Arg amino acid substitution was identified in the reviewed evidence, so PS1 was not assessed.
PS3
Published cell-based studies showed increased PI3K-pathway signaling in megalencephaly-associated mutant lines, but an exact p.Gly914Arg-specific validated functional assay meeting the VCEP PS3 requirements was not identified.
PS4
This variant was reported in at least five affected individuals with MCAP and is absent from gnomAD v2.1 and v4.1, so case enrichment evidence is present.
PM5
No different established pathogenic missense change at codon Gly914 was identified in the reviewed evidence, so PM5 was not assessed.
PP2
This VCEP allows PP2 for PIK3CA missense variants when the missense constraint z-score is greater than 3.09, but that gene-level constraint value was not provided in the reviewed materials.
Benign
BA1
This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its observed population frequency is 0%, which is below the VCEP BA1 threshold of greater than 0.0926%.
BS1
This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its observed population frequency is 0%, which is below the VCEP BS1 threshold of greater than 0.0185%.
BS2
This variant is absent from gnomAD v2.1 and gnomAD v4.1, so it does not meet the VCEP BS2 threshold of at least 3 homozygotes in population data, and no well-phenotyped unaffected family carriers were identified.
BS3
No well-established study showed normal function for p.Gly914Arg.
BP2
No cis or trans observation with another established pathogenic PIK3CA variant was identified, so BP2 was not assessed.
BP5
No alternate molecular diagnosis explaining the phenotype was identified in the reviewed evidence, so BP5 was not assessed.
N/A · 13
PVS1 · PM3 · PM4 · PM6 · PP1 · PP3 · PP4 · BS4 · BP1 · BP3 · BP4 · BP6 · BP7
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
moderate
Sources & reference links