About PIK3CA
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PIK3CA c.2176G>A, p.(Glu726Lys)
Classification
Likely pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic classification under the recorded framework.
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
PS2Moderate
PS2 · moderate
The variant was identified as de novo in one MCAP patient (162-001P) with confirmed maternity and paternity, satisfying PS2_Moderate per VCEP Criteria 1. Postzygotic mosaicism was demonstrated in two additional unrelated MCAP patients (LR08-261 at 12% in blood and 41% in buccal swab; LR06-333 at 14% in LCL), fulfilling the mosaic nature expected for this disorder.
PS4Strong
PS4 · strong
The variant has been observed in four independently reported MCAP patients with megalencephaly and brain malformations, all absent from population controls (PM2 met). Multiple cases with a highly specific phenotype (megalencephaly-capillary malformation with brain overgrowth) support PS4_Strong under the Brain Malformations VCEP point-based framework.
PM2Supporting
PM2 · supporting
The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting the VCEP PM2_Supporting threshold (absent/rare in controls, ≤1 individual).
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: Likely pathogenic
Brain Malformations Specification Tavtigian point framework v1.1.0 point-based framework: PS2 moderate (+2) + PS4 strong (+4) + PM2 supporting (+1) + PP5 supporting (+1) = 8 points, which maps to Likely Pathogenic.
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.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.020 maximum delta
Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
8 reported laboratory submissions
8 Pathogenic.
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
167 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV55875460, n = 167 times).
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.
26 criteria with recorded statuses: 4 met · 9 not met · 2 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_006218.3:c.2176G>A (p.Glu726Lys) is a missense variant in PIK3CA exon 14 that is absent from gnomAD population databases (PM2_Supporting).
The variant was identified as a confirmed de novo event in one MCAP patient and as a postzygotic mosaic mutation in two additional unrelated MCAP patients, consistent with the known gain-of-function disease mechanism (PS2_Moderate).
Four independently reported patients with megalencephaly-capillary malformation syndrome and brain overgrowth phenotypes carry this variant, with strong phenotype specificity for the disorder (PS4_Strong).
This variant has been classified as Pathogenic by the ClinGen Brain Malformations Variant Curation Expert Panel after expert panel review (ClinVar Variation ID: 376476).
Using the Brain Malformations VCEP Tavtigian point framework (Path Supporting +1, Path Moderate +2, Path Strong +4, Path Very Strong +8), the assigned criteria yield a total of 7 points, which falls within the Likely Pathogenic range (6 to 9 points). The expert panel classification of Pathogenic likely reflects additional criteria such as PM1 or PS3 applied with access to the VCEP functional assay spreadsheet and Table 2A phenotype point values.
No criteria match.
Met · 4
PS2 ModerateThe variant was identified as de novo in one MCAP patient (162-001P) with confirmed maternity and paternity, satisfying PS2_Moderate per VCEP Criteria 1. Postzygotic mosaicism was demonstrated in two additional unrelated MCAP patients (LR08-261 at 12% in blood and 41% in buccal swab; LR06-333 at 14% in LCL), fulfilling the mosaic nature expected for this disorder. Details ▾Hide ▴
Evidence considered
- 162-001P: de novo c.2176G>A (p.Glu726Lys) with confirmed parentage in MCAP patient (PMID:22729224 Table 1)
- LR08-261: mosaic
- 12% mutant allele in blood
- 41% in buccal swab (PMID:22729224 Table 2)
- LR06-333: mosaic
- 14% mutant allele in LCL
- 15% in saliva (PMID:22729224 Table 2)
Still missing
- Tissue-specific allele fraction data not available for the confirmed de novo case 162-001P
- PS2_Strong requires both Criteria 1 and 2 in the same individual.
Sources
PS4 StrongThe variant has been observed in four independently reported MCAP patients with megalencephaly and brain malformations, all absent from population controls (PM2 met). Multiple cases with a highly specific phenotype (megalencephaly-capillary malformation with brain overgrowth) support PS4_Strong under the Brain Malformations VCEP point-based framework. Details ▾Hide ▴
Evidence considered
- 3 MCAP patients in PMID:22729224: 162-001P
- LR08-261
- LR06-333 all with megalencephaly
- capillary malformations
- and brain imaging abnormalities
- 1 MCAP patient in PMID:29549527 (Patient 3): focal hemimegalencephaly
- perisylvian polymicrogyria
- capillary malformation
- seizures
- Variant is absent from gnomAD v2.1 and v4.1
- satisfying PM2 prerequisite
Still missing
- Precise PS4 point total cannot be calculated without VCEP Table 2A phenotype point values
- strength assignment is a conservative estimate based on 4 independently reported cases with brain malformation phenotypes.
Sources
PM2 SupportingThe variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting the VCEP PM2_Supporting threshold (absent/rare in controls, ≤1 individual). Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
- Absent from gnomAD-Canada v1.0
Sources
Not met · 9 · evaluated, threshold not reached
PS1 No alternate nucleotide change producing the same p.Glu726Lys amino acid substitution has been identified as a previously established pathogenic variant. c.2176G>A is the only nucleotide change reported at this residue. Details ▾Hide ▴
Evidence considered
- No alternate nucleotide change at codon 726 producing p.Glu726Lys was identified in ClinVar
- COSMIC
- or the reviewed literature.
PM1 Residue Glu726 lies outside both PIK3CA critical functional domains specified in VCEP Table 4 (kinase domain AA 322-483 and kinase domain AA 797-1068). While the variant resides in a statistically significant Cancer Hotspot, the VCEP restricts PM1_Supporting to Table 4 approved domain membership. Details ▾Hide ▴
Evidence considered
- VCEP Table 4 domains for PIK3CA: AA 322-483 and AA 797-1068
- Residue 726 is not within either approved domain
- Cancer Hotspots identifies the region as statistically significant but this does not satisfy the VCEP domain-based PM1 requirement
Sources
PM5 No pathogenic missense variant at residue Glu726, other than the queried E726K, was identified in ClinVar or the reviewed literature. PM5 requires a different pathogenic missense change at the same amino acid residue. Details ▾Hide ▴
Evidence considered
- PM5 candidate search identified zero comparator variants at residue 726.
BA1 The variant is absent from gnomAD. The VCEP BA1 threshold of >0.0926% allele frequency is not reached. Details ▾Hide ▴
Evidence considered
- Allele frequency is 0.0 in gnomAD v2.1 and v4.1
- VCEP BA1 threshold is >0.0926%.
Sources
BS1 The variant is absent from gnomAD. The VCEP BS1 threshold of >0.0185% allele frequency is not reached. Details ▾Hide ▴
Evidence considered
- Allele frequency is 0.0 in population databases
- VCEP BS1 threshold is >0.0185%.
Sources
BS2 The variant is absent from gnomAD with zero homozygotes. No evidence of three or more well-phenotyped heterozygous healthy family members. BS2 criteria not satisfied. Details ▾Hide ▴
Evidence considered
- Zero homozygotes in gnomAD
- no healthy adult carriers identified.
Sources
BS3 No well-established in vitro or in vivo functional studies demonstrate a benign effect for this variant. All available functional evidence in the PI3K pathway indicates gain-of-function effects for PIK3CA mutations in this gene region, which is inconsistent with a benign interpretation. Details ▾Hide ▴
Evidence considered
- No functional studies showing no damaging effect on protein function were identified for this variant.
BP2 No evidence was identified that this variant has been observed in cis or trans with a known pathogenic variant in PIK3CA. Details ▾Hide ▴
Evidence considered
- No reports of co-occurrence with a known pathogenic PIK3CA variant were found in the reviewed literature or ClinVar.
BP5 No evidence was identified that any affected individual carrying this variant has an alternate molecular basis for disease. Details ▾Hide ▴
Evidence considered
- No alternate genetic diagnosis was reported in any of the four MCAP patients carrying this variant.
Not assessed · 2 · no assessment recorded
PS3 No variant-specific functional assay data for NM_006218.3:c.2176G>A (p.Glu726Lys) meeting VCEP BMVCEP quality criteria was identified. PMID:22729224 performed PI3K pathway functional assays on lymphoblastoid lines carrying other PIK3CA mutations (p.Glu453del) but did not test cells harboring E726K. PMID:29549527 identified E726K in Patient 3 primary fibroblasts but reported detailed functional data only for Patient 1 (H1047R). Details ▾Hide ▴
Evidence considered
- PMID:22729224: Functional assays (PIP3 levels
- pS6
- p4E-BP1) performed on PIK3CA p.Glu453del and PIK3R2 p.Gly373Arg lines
- not on E726K specifically.
- PMID:29549527: E726K mutation identified at 37% in Patient 3 (MCAP) fibroblasts
- functional characterization focused on Patient 1 (H1047R).
Still missing
- Variant-specific functional assay demonstrating gain-of-function effect for E726K is unavailable in the reviewed full-text literature.
- VCEP-approved functional assay spreadsheet (Supplemental Document 1) was not accessible for cross-reference.
Sources
PP2 The VCEP specifies PP2_Supporting for PIK3CA when the missense z-score exceeds 3.09. PIK3CA is a highly constrained gene with established intolerance to missense variation, but the specific gnomAD missense z-score was not provided in the evidence package and could not be independently verified. Details ▾Hide ▴
Evidence considered
- VCEP criteria specifies PP2_Supporting for PIK3CA when z-score > 3.09
- PIK3CA is qualitatively known to have high missense constraint.
Still missing
- gnomAD missense constraint z-score for PIK3CA not available in case data
- human review should confirm and apply if z > 3.09.
Sources
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 VCEPNot applicable per ClinGen Brain Malformations VCEP: the disease mechanism for PIK3CA-related brain malformations is gain of function, not loss of function. Details ▾Hide ▴
Evidence considered
- VCEP criteria.json explicitly marks PVS1 as Not Applicable for this VCEP due to GOF disease mechanism.
Sources
PM6 VCEPNot applicable per ClinGen Brain Malformations VCEP: PM6 is addressed under PS2 and is not used independently. Details ▾Hide ▴
Evidence considered
- VCEP criteria explicitly states PM6 is not applicable
- de novo evidence is assessed under PS2.
Sources
PP1 VCEPNot applicable per ClinGen Brain Malformations VCEP: disease-causing variants in these genes are germline mosaic, de novo, or postzygotic mosaic; co-segregation is not expected. Details ▾Hide ▴
PP3 VCEPNot applicable per ClinGen Brain Malformations VCEP: traditional in silico pathogenicity prediction algorithms are designed for loss-of-function mechanisms and are not validated for gain-of-function variants. Details ▾Hide ▴
Evidence considered
- VCEP marks PP3 as Not Applicable
- REVEL score of 0.442 and BayesDel score of 0.267 are noted but not used per VCEP guidance.
Sources
PP4 VCEPNot applicable per ClinGen Brain Malformations VCEP: phenotype specificity is accounted for under PS4. Details ▾Hide ▴
BS4 VCEPNot applicable per ClinGen Brain Malformations VCEP: these are de novo, germline mosaic, or postzygotic mutations; lack of segregation is not expected. Details ▾Hide ▴
BP1 VCEPNot applicable per ClinGen Brain Malformations VCEP: loss of function is not the disease mechanism for PIK3CA-related disorders. Details ▾Hide ▴
Evidence considered
- VCEP criteria marks BP1 as Not Applicable (LOF not the disease mechanism).
Sources
BP4 N/ANot applicable per ClinGen Brain Malformations VCEP: BP4 is restricted to synonymous, intronic (non-canonical splice), and UTR variants when two of three splicing prediction tools predict no impact. This is a missense variant and does not qualify. Details ▾Hide ▴
Evidence considered
- VCEP BP4 specification is limited to non-coding variant types
- SpliceAI max delta score of 0.02 is noted but not applicable for BP4 on a missense variant.
Sources
BP6 VCEPNot applicable per ClinGen Brain Malformations VCEP: BP6 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
BP7 N/ANot applicable: BP7 per VCEP is restricted to synonymous, intronic (non-canonical splice), and UTR variants. This is a missense variant. Details ▾Hide ▴
PS5 N/APS5 is not a recognized ACMG/AMP criterion. This criterion does not exist in the standard framework. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- PIK3CA
- Transcript
- NM_006218.3
- Coding (HGVS c.)
- NM_006218.3:c.2176G>A
- Protein (HGVS p.)
- NP_006209.2:p.(Glu726Lys)
- GRCh38
- chr3:179221146 G>A
- GRCh37
- chr3:178938934 G>A
- ClinVar
- 376476
- COSMIC
- COSV55875460
Gene diagram
Every interpreted variant in PIK3CA, mapped onto the exon structure of NM_006218.3. Select a row to find it on the plot.
PIK3CANM_006218.3
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
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.442
- BayesDel
- 0.267
How the predictions were used
PP3 VCEPNot applicable per ClinGen Brain Malformations VCEP: traditional in silico pathogenicity prediction algorithms are designed for loss-of-function mechanisms and are not validated for gain-of-function variants. Details ▾Hide ▴
Evidence considered
- VCEP marks PP3 as Not Applicable
- REVEL score of 0.442 and BayesDel score of 0.267 are noted but not used per VCEP guidance.
Sources
BP4 N/ANot applicable per ClinGen Brain Malformations VCEP: BP4 is restricted to synonymous, intronic (non-canonical splice), and UTR variants when two of three splicing prediction tools predict no impact. This is a missense variant and does not qualify. Details ▾Hide ▴
Evidence considered
- VCEP BP4 specification is limited to non-coding variant types
- SpliceAI max delta score of 0.02 is noted but not applicable for BP4 on a missense variant.
Sources
BP7 N/ANot applicable: BP7 per VCEP is restricted to synonymous, intronic (non-canonical splice), and UTR variants. This is a missense variant. Details ▾Hide ▴
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.
10 paper records listed. 2 cited in the classification.
Cited in the classification
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PMID 22729224 ↗De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes.Rivière JB et al. · 2012 Jun 24NM_006218.3:c.2176G>A (p.Glu726Lys) identified as a de novo or postzygotic mosaic mutation in three unrelated MCAP patients (162-001P, LR08-261, LR06-333). Deep sequencing confirmed mosaicism with mutant allele fractions ranging from 12% to 41% across tissues. Functional assays on lymphoblastoid lines from other PIK3CA mutation carriers demonstrated increased PIP3 levels and elevated PI3K-mTOR signaling, consistent with gain of function.→ PS2 → PS4 Names this variant
Source detail
MCAP 162-001P PIK3CA chr3:178938934 G>A c.2176G>A p.Glu726Lys De novo
Location Table 1 (mutation list, 3 occurrences of c.2176G>A); Table 2 (deep sequencing confirmation of mosaicism for LR08-261 and LR06-333); Results para 2
Context Lymphoblastoid cell lines from MCAP patients with other PIK3CA mutations; PIP3 immunostaining, S6/4E-BP1 phosphorylation western blots; PI3K inhibitor PI-103 treatment
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PMID 29549527 ↗In vitro efficacy of ARQ 092, an allosteric AKT inhibitor, on primary fibroblast cells derived from patients with PIK3CA-related overgrowth spectrum (PROS).Ranieri C et al. · 2018 MayNM_006218.3:c.2176G>A identified in Patient 3 (MCAP), a 17-year-old boy with focal hemimegalencephaly, perisylvian polymicrogyria, capillary malformations, and refractory seizures. Mutation present at 37% allele frequency in cultured primary fibroblasts from affected skin. The paper focused functional characterization on Patient 1 (H1047R) and did not report variant-specific functional data for E726K.→ PS4 Names this variant
Source detail
3 MCAP c.2176G > A p.Glu726Gly 37 37 N/A N/A
Location Table 1 (Patient 3: MCAP, c.2176G>A, p.Glu726Gly [sic - likely typo for Lys], 37% in biopsy/cells); Subjects and Methods, Patient 3 description
Context Primary fibroblasts from affected skin biopsies; targeted deep sequencing of 21 PI3K/AKT/mTOR pathway genes; AKT inhibitor ARQ 092 treatment; WST-1 proliferation assays; western blot for pAKT/pAKT1S1/pRPS6
Other recorded publications
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PMID 29533785 ↗Systematic Functional Annotation of Somatic Mutations in Cancer.Systematic functional annotation of somatic mutations in cancer using a moderate-throughput functional genomic platform. The paper screened cancer-associated mutations but NM_006218.3:c.2176G>A (p.Glu726Lys) was not specifically reported or functionally characterized.Does not name this variant
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PMID 24497998 ↗Megalencephaly syndromes: exome pipeline strategies for detecting low-level mosaic mutations.Tapper WJ et al. · 2014No paper-specific finding is recorded.
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PMID 25626707 ↗Whole-genome sequencing in newborn screening? A statement on the continued importance of targeted approaches in newborn screening programmes.No paper-specific finding is recorded.
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PMID 25730230 ↗Expanded carrier screening in reproductive medicine-points to consider: a joint statement of the American College of Medical Genetics and Genomics, American College of Obstetricians and Gynecologists, National Society of Genetic Counselors, Perinatal Quality Foundation, and Society for Maternal-Fetal Medicine.Joint statement on expanded carrier screening in reproductive medicine. This is a policy statement that does not report primary genetic data on PIK3CA variants.Does not name this variant
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PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.ACMG/AMP standards and guidelines for the interpretation of sequence variants. This is a methods guideline paper that does not report primary data on specific variants.Does not name this variant
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PMID 23246288 ↗Germline PIK3CA and AKT1 mutations in Cowden and Cowden-like syndromes.Orloff MS et al. · 2013Germline PIK3CA and AKT1 mutations in Cowden and Cowden-like syndromes. The paper screened PIK3CA in Cowden syndrome patients and identified germline variants including H1047R and others, but NM_006218.3:c.2176G>A (p.Glu726Lys) was not identified in the study cohort.Does not name this variant
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PMID 23037933 ↗Including the initial newborn screening bloodspot collection device serial number on birth certificates: basis and recommendations from the Secretary of Health and Human Services' Advisory Committee on Heritable Disorders in Newborns and Children.No paper-specific finding is recorded.
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PMID 24394680 ↗Parental permission for pilot newborn screening research: guidelines from the NBSTRN.No paper-specific finding is recorded.
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
Recorded maximum delta 0.020
Open source ↗
ClinVar
8 Pathogenic
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…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/3-179221146-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006218.3%3Ac.2176…
- OncoKB ↗www.oncokb.org/gene/PIK3CA/E726K
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=119880437
- 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.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Pathogenic (8 clinical laboratories) and as Pathogenic by ClinGen Brain Malformations Variant Curation Expert Panel (expert panel). (ClinVarID = 376476)
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 = 167 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.