About PIK3CA
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PIK3CA c.2176G>A, p.(Glu726Lys)
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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Supporting
PM2 · supporting
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.
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: PM2 supporting (+1) + PP5 supporting (+1) = 2 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: Inconclusive; curated oncogenicity label: Inconclusive.
No listed criterion applied
OncoKB ↗
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: 2 met · 5 not met · 8 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.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.
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.
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.
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.
No criteria match.
Met · 2
PM2 SupportingThis 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. Details ▾Hide ▴
Rule
VCEP PM2 is Supporting for absent/rare population frequency with one person maximum.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
Sources
PP5 SupportingExpert panel ClinGen Brain Malformations Variant Curation Expert Panel classified as Pathogenic. Details ▾Hide ▴
Not met · 5 · evaluated, threshold not reached
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. Details ▾Hide ▴
Rule
VCEP PM1 for PIK3CA is Supporting only and requires location within a Table 4 approved domain.
Evidence considered
- Protein consequence p.Glu726Lys.
- VCEP Table 4 approved PIK3CA PM1 domains: aa 322-483 and aa 797-1068.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
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. Details ▾Hide ▴
Rule
VCEP BA1 requires allele frequency >0.0926%.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
Sources
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. Details ▾Hide ▴
Rule
VCEP BS1 requires allele frequency >0.0185%.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
Sources
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. Details ▾Hide ▴
Rule
VCEP BS2 requires ≥3 homozygotes in gnomAD or ≥3 well-phenotyped family members.
Evidence considered
- Variant absent from gnomAD.
- No unaffected carrier data were identified.
Sources
BS3 No well-established functional study in the retrieved materials showed normal or benign function for p.Glu726Lys, so BS3 is not met. Details ▾Hide ▴
Rule
VCEP BS3 follows SVI functional-evidence guidance and requires well-established studies supporting no damaging effect.
Evidence considered
- Relevant functional literature was identified
- but no normal-function result was provided in the retrieved materials.
Still missing
- Need direct review of any variant-specific functional assays to confirm whether normal function has ever been shown.
Sources
Not assessed · 8 · no assessment recorded
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. Details ▾Hide ▴
Rule
VCEP PS1 unchanged from ACMG/AMP: same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Evidence considered
- VCEP framework reviewed for PS1 applicability.
Still missing
- Confirm whether any alternate nucleotide change at codon 726 producing the same amino acid substitution has been established as pathogenic under this VCEP framework.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
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. Details ▾Hide ▴
Rule
VCEP PS2: Strong requires both confirmed parental absence and tissue-distribution evidence; Moderate requires one of these specified scenarios.
Evidence considered
- VCEP PS2 requires specific de novo/mosaic evidence.
- Abstract-level literature supports de novo/postzygotic PIK3CA disease mechanism but not variant-specific PS2 scoring details.
Still missing
- Need exact p.Glu726Lys case reports with confirmed maternity and paternity.
- Need tissue-specific allele fraction data showing presence in affected tissue and absence or lower fraction in another tissue
- if used.
Sources
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. Details ▾Hide ▴
Rule
VCEP PS3 follows SVI functional-evidence guidance with Brain Malformations specifications for assay quality and interpretation.
Evidence considered
- OncoKB cites variant-relevant functional literature.
- Functional and disease-mechanism papers were identified but not with extractable assay-level results for scoring.
Still missing
- Need direct review of variant-specific functional assay results for p.Glu726Lys.
- Need assay validation details sufficient to map the evidence to VCEP/SVI PS3 requirements.
Sources
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. Details ▾Hide ▴
Rule
VCEP PS4 is phenotype-point based and requires PM2 first; strength depends on total Table 2A/Table 2B points.
Evidence considered
- ClinVar reports pathogenic submissions including expert panel review.
- Disease literature and ClinVar citations show affected-case reporting.
- PM2 prerequisite is supported by absence from gnomAD.
Still missing
- Need exact count of independent affected individuals with p.Glu726Lys.
- Need phenotype-specific Table 2A point assignments for each report.
- Need total PS4 point sum to determine Supporting
- Moderate
- Strong
- or Very Strong strength.
Sources
clinvar ↗PMID:22729224 ↗PMID:24497998 ↗cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1gnomad_v2 ↗gnomad_v4 ↗
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. Details ▾Hide ▴
Rule
VCEP PM5 unchanged from ACMG/AMP: novel missense change at an amino acid residue where a different pathogenic missense change has been seen before.
Evidence considered
- VCEP framework reviewed for PM5 applicability.
Still missing
- Need codon-specific review for other established pathogenic substitutions at residue 726 under this VCEP framework.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
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. Details ▾Hide ▴
Rule
VCEP PP2 applies to PIK3CA if missense constraint z-score is >3.09.
Evidence considered
- VCEP PP2 rule requires missense constraint z-score >3.09.
Still missing
- Need the PIK3CA missense constraint z-score used by the VCEP framework.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
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. Details ▾Hide ▴
Rule
VCEP BP2 unchanged from ACMG/AMP: observed in cis or trans with a known pathogenic variant in the same gene.
Evidence considered
- VCEP framework reviewed for BP2 applicability.
Still missing
- Need phasing data or published co-occurrence evidence.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
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. Details ▾Hide ▴
Rule
VCEP BP5 unchanged from ACMG/AMP: variant found in a case with an alternate molecular basis for disease.
Evidence considered
- VCEP framework reviewed for BP5 applicability.
Still missing
- Need evidence for an alternate molecular basis for disease in the reported individual(s)
- if present.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable for PIK3CA in the Brain Malformations VCEP framework because the disease mechanism is gain of function, and this missense variant is not a null-variant type. Details ▾Hide ▴
Rule
VCEP PVS1 not applicable for PIK3CA because the disease mechanism is gain of function.
Evidence considered
- VCEP states PVS1 is not applicable for this gene-disease mechanism.
- Variant is a missense substitution
- not a canonical null variant.
Sources
PM3 N/APM3 is not applicable in the Brain Malformations VCEP specification for this gene-disease context. Details ▾Hide ▴
PM4 N/APM4 is not applicable in the Brain Malformations VCEP specification for this gene-disease context. Details ▾Hide ▴
PM6 N/APM6 is not applicable in the Brain Malformations VCEP specification. Details ▾Hide ▴
PP1 N/APP1 is not applicable in the Brain Malformations VCEP specification for this gene-disease context. Details ▾Hide ▴
PP3 N/APP3 is not applicable for PIK3CA gain-of-function missense variants in the Brain Malformations VCEP framework. Although SpliceAI predicts no significant splice impact (max delta score 0.02), REVEL is 0.442, and BayesDel is 0.266518, the VCEP does not use traditional pathogenicity prediction algorithms for this gain-of-function mechanism. Details ▾Hide ▴
Rule
VCEP PP3 not applicable for these GOF variants because traditional prediction algorithms focus on LOF mechanisms.
Evidence considered
- SpliceAI max delta score 0.02.
- REVEL score 0.442.
- BayesDel score 0.266518.
Sources
PP4 N/APP4 is not applicable in the Brain Malformations VCEP specification because phenotype specificity is incorporated into the PS4 point-based framework. Details ▾Hide ▴
Rule
VCEP PP4 not applicable.
Evidence considered
- VCEP marks PP4 as not applicable and accounts for phenotype under PS4.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
BS4 N/ABS4 is not applicable in this VCEP framework because these disorders are typically driven by de novo, germline mosaic, or postzygotic mutations rather than informative multigenerational segregation patterns. Details ▾Hide ▴
Rule
VCEP BS4 not applicable.
Evidence considered
- VCEP marks BS4 as not applicable.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
BP1 N/ABP1 is not applicable for PIK3CA in this gain-of-function disease context. Details ▾Hide ▴
Rule
VCEP BP1 not applicable.
Evidence considered
- Index guidance states BP1 is not applicable because the disease mechanism is gain of function.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
BP3 N/ABP3 is not applicable in the Brain Malformations VCEP specification for this gene-disease context. Details ▾Hide ▴
BP4 N/AThis is a missense variant. Under the Brain Malformations VCEP specification, BP4 is limited to synonymous, intronic noncanonical splice-site, and UTR variants evaluated for predicted lack of splicing impact. Details ▾Hide ▴
Rule
VCEP BP4 applies only to synonymous, intronic noncanonical splice-site, or UTR variants when splicing tools predict no impact.
Evidence considered
- Variant consequence is missense p.Glu726Lys.
- SpliceAI max delta score is 0.02
- but BP4 is not used for missense variants in this VCEP framework.
Sources
BP6 N/ABP6 is not applicable in the Brain Malformations VCEP specification. Details ▾Hide ▴
BP7 N/AThis is a missense variant rather than a synonymous, intronic, or UTR variant, so BP7 is not applicable under the Brain Malformations VCEP specification. Details ▾Hide ▴
Rule
VCEP BP7 applies to synonymous, intronic noncanonical splice-site, and UTR variants with low conservation criteria.
Evidence considered
- Variant consequence is missense p.Glu726Lys.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
Identifiers
- Gene
- PIK3CA
- Transcript
- NM_006218.2
- Coding (HGVS c.)
- NM_006218.2:c.2176G>A
- Protein (HGVS p.)
- NP_006209.2:p.(Glu726Lys)
- GRCh38
- chr3:179221146 G>A
- GRCh37
- chr3:178938934 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 for PIK3CA gain-of-function missense variants in the Brain Malformations VCEP framework. Although SpliceAI predicts no significant splice impact (max delta score 0.02), REVEL is 0.442, and BayesDel is 0.266518, the VCEP does not use traditional pathogenicity prediction algorithms for this gain-of-function mechanism. Details ▾Hide ▴
Rule
VCEP PP3 not applicable for these GOF variants because traditional prediction algorithms focus on LOF mechanisms.
Evidence considered
- SpliceAI max delta score 0.02.
- REVEL score 0.442.
- BayesDel score 0.266518.
Sources
BP4 N/AThis is a missense variant. Under the Brain Malformations VCEP specification, BP4 is limited to synonymous, intronic noncanonical splice-site, and UTR variants evaluated for predicted lack of splicing impact. Details ▾Hide ▴
Rule
VCEP BP4 applies only to synonymous, intronic noncanonical splice-site, or UTR variants when splicing tools predict no impact.
Evidence considered
- Variant consequence is missense p.Glu726Lys.
- SpliceAI max delta score is 0.02
- but BP4 is not used for missense variants in this VCEP framework.
Sources
BP7 N/AThis is a missense variant rather than a synonymous, intronic, or UTR variant, so BP7 is not applicable under the Brain Malformations VCEP specification. Details ▾Hide ▴
Rule
VCEP BP7 applies to synonymous, intronic noncanonical splice-site, and UTR variants with low conservation criteria.
Evidence considered
- Variant consequence is missense p.Glu726Lys.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.442. BayesDel score = 0.266518.
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/376476/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-178938934-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-179221146-G-A?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006218.2%3Ac.2176…
- OncoKB ↗www.oncokb.org/gene/PIK3CA/E726K
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=108144730
- 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 (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
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Inconclusive; curated oncogenicity label: Inconclusive.
Somatic
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55875460, n = 150 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.