About PIK3CA
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PIK3CA c.1624G>A, p.(Glu542Lys)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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.
01The reasoning
How it was classified
The recorded framework is ClinGen PIK3CA VCEP v1.1.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 4
Benign evidence criteria: 0
Pathogenic criteria applied · 4
PS3Supporting
PS3 · supporting
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.
PM2Supporting
PM2 · supporting
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.
PM5Moderate
PM5 · moderate
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.
PP5Supporting
PP5 · supporting
Expert panel ClinGen Brain Malformations Variant Curation Expert Panel classified as Pathogenic.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
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.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
No listed criterion applied
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Functional evidence
Statement recorded
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 assessed
No COSMIC evidence statement is recorded in this case.
Cancer Hotspots
This variant lies in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen PIK3CA VCEP v1.1.0, with the data and sources behind each one.
28 criteria with recorded statuses: 4 met · 7 not met · 4 not assessed · 13 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports rarity in population reference datasets.
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.
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.
No criteria match.
Met · 4
PS3 SupportingIn 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. Details ▾Hide ▴
Rule
PS3_Supporting
Evidence considered
- PMID:16432179: 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
Still missing
- The reviewed materials did not provide enough assay-validation detail to justify upgrading above Supporting strength in this pass.
Sources
PM2 SupportingThis 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. Details ▾Hide ▴
Rule
PM2_Supporting
Evidence considered
- gnomAD v2.1 absent
- gnomAD v4.1 absent
- VCEP PM2 strength is Supporting
Sources
PM5 ModerateOther 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. Details ▾Hide ▴
Rule
PM5_Moderate
Evidence considered
- ClinVar codon-542 review identified pathogenic or likely pathogenic alternate missense substitutions at Glu542.
Still missing
- Independent confirmation of each comparator variant's evidence base would further strengthen this assessment.
Sources
PP5 SupportingExpert panel ClinGen Brain Malformations Variant Curation Expert Panel classified as Pathogenic. Details ▾Hide ▴
Not met · 7 · evaluated, threshold not reached
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. Details ▾Hide ▴
Evidence considered
- ClinVar review of PIK3CA codon 542 did not identify an alternate nucleotide change encoding p.(Glu542Lys).
Sources
PM1 The Brain Malformations VCEP limits PM1 for PIK3CA to Table 4 approved domains at amino acids 322-483 and 797-1068. This missense variant affects residue 542, which is outside those approved intervals, so PM1 is not met. Details ▾Hide ▴
Evidence considered
- PIK3CA Table 4 approved domains: aa 322-483 and aa 797-1068
- Variant residue: Glu542
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
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%. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 absent
- gnomAD v4.1 absent
- BA1 threshold >0.0926%
Sources
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%. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 absent
- gnomAD v4.1 absent
- BS1 threshold >0.0185%
Sources
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. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 absent
- gnomAD v4.1 absent
- VCEP BS2 threshold requires >=3 homozygotes or >=3 unaffected heterozygous family members
Sources
BS3 Available functional evidence does not show a normal or no-damaging effect. In published functional studies, PIK3CA E542K increased oncogenic activity, activated downstream AKT/TOR signaling, and showed gain-of-function behavior relative to wild type, which argues against BS3. Details ▾Hide ▴
Evidence considered
- PMID:16432179: E542K oncogenic in vivo with Akt pathway activation
- PMID:17376864: helical-domain mutants show gain of function with transformation
- Akt/TOR activation
- and increased lipid kinase activity
- PMID:26627007: variant-specific phenotyping supports oncogenic activity assessment in PIK3CA
Sources
BP5 No alternate molecular basis for the reported phenotype was identified in the reviewed evidence, so BP5 is not met. Details ▾Hide ▴
Evidence considered
- No alternate molecular diagnosis was documented in reviewed sources.
Sources
Not assessed · 4 · no assessment recorded
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. PS2 cannot be applied from the reviewed evidence. Details ▾Hide ▴
Evidence considered
- VCEP PS2 requires confirmed parental absence and/or tissue mosaic comparison.
- ClinVar summary confirms clinical reporting but does not provide the required case-level de novo/tissue evidence here.
Still missing
- Case-level parental testing data were not identified.
- Case-level tissue-comparison allele fraction data were not identified.
Sources
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. However, the reviewed evidence does not provide a direct Table 2A phenotype-point tally needed to assign a PS4 strength under the Brain Malformations VCEP, so PS4 was not independently applied in this pass. Details ▾Hide ▴
Evidence considered
- ClinVar expert panel pathogenic classification
- gnomAD v2.1 absent
- gnomAD v4.1 absent
- VCEP PS4 requires phenotype points after PM2
Still missing
- Published case counts were not converted into a Table 2A/Table 2B point total.
- Phenotype-specific point assignments for individual cases were not extracted.
Sources
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. Details ▾Hide ▴
Evidence considered
- VCEP PP2 threshold requires missense z-score >3.09.
Still missing
- PIK3CA missense constraint z-score was not available in the reviewed materials.
Sources
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. Details ▾Hide ▴
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable for PIK3CA in the Brain Malformations VCEP because the disease mechanism is gain of function rather than loss of function, and this variant is a missense substitution rather than a null variant. Details ▾Hide ▴
Evidence considered
- VCEP states PVS1 is not applicable for PIK3CA GOF disease mechanism.
- Variant type is missense
- outside generic null-variant buckets.
Sources
PM3 N/APM3 is not applicable because PIK3CA-related brain malformation disorders are not evaluated as recessive conditions in this VCEP framework. Details ▾Hide ▴
Evidence considered
- Brain Malformations VCEP marks PM3 not applicable for heterozygous disease mechanism.
Sources
PM4 N/APM4 is not applicable under the Brain Malformations VCEP because this variant is not an in-frame insertion/deletion or stop-loss variant. Details ▾Hide ▴
PM6 N/APM6 is not applicable in this VCEP because de novo and mosaic evidence is handled through the PS2 framework instead. Details ▾Hide ▴
Evidence considered
- Brain Malformations VCEP marks PM6 not applicable.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
PP1 N/APP1 is not applicable under the Brain Malformations VCEP because disease-causing variants are typically mosaic or de novo rather than supported by informative familial segregation. Details ▾Hide ▴
Evidence considered
- Brain Malformations VCEP marks PP1 not applicable.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
PP3 N/APP3 is not applicable under the Brain Malformations VCEP for PIK3CA gain-of-function disorders because conventional missense pathogenicity algorithms are not considered reliable for this mechanism. REVEL was 0.439, BayesDel was 0.232897, and SpliceAI max delta score was 0.00, but these results were not used to apply PP3. Details ▾Hide ▴
Evidence considered
- REVEL 0.439
- BayesDel 0.232897
- SpliceAI max delta 0.00
- VCEP states PP3 not applicable for GOF variants
Sources
PP4 N/APP4 is not applicable under the Brain Malformations VCEP because phenotype specificity is incorporated into the PS4 point-based framework. Details ▾Hide ▴
Evidence considered
- Brain Malformations VCEP marks PP4 not applicable.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
BS4 N/ABS4 is not applicable under the Brain Malformations VCEP because these disorders are typically caused by de novo, germline mosaic, or post-zygotic variants rather than informative multigenerational segregation patterns. Details ▾Hide ▴
Evidence considered
- Brain Malformations VCEP marks BS4 not applicable.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
BP1 N/ABP1 is not applicable for PIK3CA in this VCEP because disease is not primarily caused by truncating loss-of-function variants. Details ▾Hide ▴
Evidence considered
- Brain Malformations VCEP marks BP1 not applicable for GOF mechanism.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
BP3 N/ABP3 is not applicable under the Brain Malformations VCEP for these genes because the relevant exon regions are not repetitive regions without known function. Details ▾Hide ▴
Evidence considered
- Brain Malformations VCEP marks BP3 not applicable.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
BP4 N/ABP4 is limited by this VCEP to synonymous, intronic, and non-coding variants assessed with splicing predictors and is not applicable to this missense variant, even though SpliceAI predicts no splice effect. Details ▾Hide ▴
Evidence considered
- Variant type is missense
- SpliceAI max delta 0.00
- VCEP BP4 applicability excludes missense variants
Sources
BP6 N/ABP6 is not used under current ClinGen recommendations and is marked not applicable by the Brain Malformations VCEP. Details ▾Hide ▴
Evidence considered
- Brain Malformations VCEP marks BP6 not applicable.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
BP7 N/ABP7 is restricted to synonymous, intronic, or non-coding variants with no predicted splice effect and does not apply to this missense variant. Details ▾Hide ▴
Identifiers
- Gene
- PIK3CA
- Transcript
- NM_006218.2
- Coding (HGVS c.)
- NM_006218.2:c.1624G>A
- Protein (HGVS p.)
- NP_006209.2:p.(Glu542Lys)
- GRCh38
- chr3:179218294 G>A
- GRCh37
- chr3:178936082 G>A
Gene diagram
Every interpreted variant in PIK3CA, mapped onto the exon structure of NM_006218.2. Select a row to find it on the plot.
PIK3CANM_006218.2
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in PIK3CA
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 N/APP3 is not applicable under the Brain Malformations VCEP for PIK3CA gain-of-function disorders because conventional missense pathogenicity algorithms are not considered reliable for this mechanism. REVEL was 0.439, BayesDel was 0.232897, and SpliceAI max delta score was 0.00, but these results were not used to apply PP3. Details ▾Hide ▴
Evidence considered
- REVEL 0.439
- BayesDel 0.232897
- SpliceAI max delta 0.00
- VCEP states PP3 not applicable for GOF variants
Sources
BP4 N/ABP4 is limited by this VCEP to synonymous, intronic, and non-coding variants assessed with splicing predictors and is not applicable to this missense variant, even though SpliceAI predicts no splice effect. Details ▾Hide ▴
Evidence considered
- Variant type is missense
- SpliceAI max delta 0.00
- VCEP BP4 applicability excludes missense variants
Sources
BP7 N/ABP7 is restricted to synonymous, intronic, or non-coding variants with no predicted splice effect and does not apply to this missense variant. Details ▾Hide ▴
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.439. BayesDel score = 0.232897.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/467907148
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/31944/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-178936082-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-179218294-G-A?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006218.2%3Ac.1624…
- OncoKB ↗www.oncokb.org/gene/PIK3CA/E542K
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=108143915
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
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
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Oncogenic.
Somatic
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55873227, n = 1958 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.