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
Final classification
VUS
PP5PM5PM2PS3
PIK3CA
c.1624G>A
p.Glu542Lys
This variant
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 ↗
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
PS3
supporting
Pathogenic
In published functional studies, PIK3CA E542K showed gain-of-function behavior relative to wild type, including in vivo tumor formation with increased AKT pathway activation and constitutive activation of AKT/TOR signaling with transforming activity. This supports an abnormal activating effect consistent with the known disease mechanism and meets PS3 at Supporting strength in this pass.
PMID:16432179: E542K oncogenic in vivo and activates Akt pathwayPMID:17376864: gain-of-function with transformationAkt/TOR activation
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the Brain Malformations VCEP requirement for PM2 and supports PM2 at Supporting strength.
gnomAD v2.1 absentgnomAD v4.1 absentVCEP PM2 strength is Supporting
PM5
moderate
review
Pathogenic
Other missense changes affecting the same residue have been reported in ClinVar as pathogenic or likely pathogenic, including p.(Glu542Gln), p.(Glu542Ala), and p.(Glu542Gly). This supports PM5 for a missense change at residue 542.
ClinVar codon-542 review identified pathogenic or likely pathogenic alternate missense substitutions at Glu542.
Assessed · not applied
· 7 not met · 4 not assessed
Pathogenic
PS1
No previously established pathogenic variant producing the same p.(Glu542Lys) amino acid change by a different nucleotide change was identified in the reviewed ClinVar evidence, so PS1 is not met.
PS2
Available evidence does not document confirmed maternity and paternity with absence of the variant in parents, and it does not provide a verified comparison showing the variant present in affected tissue and absent from or at lower allele fraction in another tissue.
PS4
This variant has been reported in affected individuals and is classified as pathogenic in ClinVar by the Brain Malformations expert panel, and it is absent from gnomAD, which supports the PM2 prerequisite.
PM1
The Brain Malformations VCEP limits PM1 for PIK3CA to Table 4 approved domains at amino acids 322-483 and 797-1068.
PP2
This is a missense variant in a gene for which the VCEP allows PP2 when the missense constraint z-score is greater than 3.09, but the reviewed evidence did not provide the gene-level z-score needed to apply PP2 in this pass.
Benign
BA1
This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore is below the Brain Malformations VCEP BA1 threshold of greater than 0.0926%.
BS1
This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore is below the Brain Malformations VCEP BS1 threshold of greater than 0.0185%.
BS2
This variant is absent from gnomAD v2.1 and gnomAD v4.1, and no evidence identified at least 3 homozygotes in population databases or at least 3 well-phenotyped unaffected heterozygous relatives required for BS2.
BS3
Available functional evidence does not show a normal or no-damaging effect.
BP2
No phase data were identified showing this variant in cis or trans with a known pathogenic PIK3CA variant, so BP2 cannot be assessed from the reviewed evidence.
BP5
No alternate molecular basis for the reported phenotype was identified in the reviewed evidence, so BP5 is not met.
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 (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.
Cancer-specific mutations in PIK3CA are oncogenic in vivo.
Found
E542K oncogenic in vivo and activates Akt pathway PMID:17376864: gain-of-function with transformation Akt/TOR activation and enhanced lipid kinase activity PMID:26627007: variant-specific functional phenotyping framework for PIK3CA
Applied to
→PS3
supporting
Rare cancer-specific mutations in PIK3CA show gain of function.
Found
E542K oncogenic in vivo and activates Akt pathway PMID:17376864: gain-of-function with transformation Akt/TOR activation and enhanced lipid kinase activity PMID:26627007: variant-specific functional phenotyping framework for PIK3CA
Applied to
→PS3
supporting
Identification of Variant-Specific Functions of PIK3CA by Rapid Phenotyping of R
Found
E542K oncogenic in vivo and activates Akt pathway PMID:17376864: gain-of-function with transformation Akt/TOR activation and enhanced lipid kinase activity PMID:26627007: variant-specific functional phenotyping framework for PIK3CA
Applied to
→PS3
supporting
Sources & reference links