The PIK3CA c.2176G>A (p.Glu726Lys, p.E726K) variant has been observed in somatic cancers in COSMIC (COSV55875460, n=150) and has been reported in ClinVar as Pathogenic, including expert-panel review by the ClinGen Brain Malformations Variant Curation Expert Panel.1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports PM2 at Supporting strength under the Brain Malformations VCEP population rule.2 Published PIK3CA disease-mechanism and functional literature was identified, but the retrieved materials do not provide enough variant-specific assay detail to assign PS3 or BS3 for p.Glu726Lys without direct full-text review.3 In silico data show no predicted splice disruption by SpliceAI (max delta score 0.02), with REVEL 0.442 and BayesDel 0.266518; however, PP3 is not applicable for PIK3CA gain-of-function variants in this VCEP framework and BP4 is restricted to non-missense splicing-context variants.4
Final classification
VUS
PM2PP5
PIK3CA
c.2176G>A
p.Glu726Lys
This variant
The PIK3CA c.2176G>A (p.Glu726Lys, p.E726K) variant has been observed in somatic cancers in COSMIC (COSV55875460, n=150) and has been reported in ClinVar as Pathogenic, including expert-panel review by the ClinGen Brain Malformations Variant Curation Expert Panel.
Brain Malformations Specification Tavtigian point framework v1.1.0 point-based framework: PM2 supporting (+1) + PP5 supporting (+1) = 2 points, which maps to VUS.
Classification rationale
PM2PP5
VUS
PIK3CA c.2176G>A
PM2 + PP5
→
VUS
4
spliceai ↗revelbayesdelcspec ↗
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 · 2 applied · 13 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 · 2
Strength
Supporting
Moderate
Strong
Very strong
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the Brain Malformations VCEP PM2 threshold of at most one person in population databases and supports PM2 at Supporting strength.
Absent from gnomAD v2.1.Absent from gnomAD v4.1.
Assessed · not applied
· 5 not met · 8 not assessed
Pathogenic
PS1
No evidence was identified showing that this missense change creates the same amino acid substitution as a previously established pathogenic variant through a different nucleotide change.
PS2
Published PIK3CA overgrowth literature supports that de novo and postzygotic mutations occur in this disease spectrum, but the retrieved materials do not provide case-level parental testing and multi-tissue allele-fraction data for p.Glu726Lys needed to assign PS2 under the Brain Malformations VCEP rules.
PS3
Functional literature relevant to PIK3CA was identified, but the retrieved materials do not provide assay-level results, validation details, or VCEP-compatible evidence strength for p.Glu726Lys, so PS3 cannot be assigned from the available record.
PS4
This variant has been reported in affected individuals and is absent from population databases, but the retrieved materials do not provide the case-level phenotype categories and point totals required to score PS4 under the Brain Malformations VCEP point system.
PM1
The p.Glu726Lys substitution is outside the PIK3CA Table 4 approved PM1 functional-domain intervals (amino acids 322-483 and 797-1068), so PM1_Supporting is not met under the Brain Malformations VCEP specification.
PM5
No validated evidence was identified in the retrieved materials showing a different pathogenic missense change at the same codon that would support PM5 for p.Glu726Lys.
PP2
The Brain Malformations VCEP allows PP2 for PIK3CA when the missense constraint z-score exceeds 3.09, but the retrieved materials do not provide the gene-level z-score needed to determine whether this threshold is met.
Benign
BA1
This variant is absent from gnomAD and therefore far below the Brain Malformations VCEP BA1 threshold of greater than 0.0926%, so BA1 is not met.
BS1
This variant is absent from gnomAD and therefore below the Brain Malformations VCEP BS1 threshold of greater than 0.0185%, so BS1 is not met.
BS2
No evidence was identified for at least 3 homozygotes in gnomAD or at least 3 well-phenotyped unaffected family members carrying this variant, so BS2 is not met.
BS3
No well-established functional study in the retrieved materials showed normal or benign function for p.Glu726Lys, so BS3 is not met.
BP2
No evidence was identified showing this variant in cis or trans with a known pathogenic PIK3CA variant, so BP2 cannot be assessed from the available materials.
BP5
No alternate molecular diagnosis was identified that would explain the phenotype independently of this variant, so BP5 cannot be assigned from the available materials.
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 (7 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 = 0.02). REVEL score = 0.442. BayesDel score = 0.266518.
Functional
Inconclusive
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Inconclusive; curated oncogenicity label: Inconclusive.
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; COSV55875460, n = 150 times).
Hotspots
This variant lies in a statistically significant hotspot.
Sources & reference links