About PIK3CA
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PIK3CA c.2740G>A, p.(Gly914Arg)
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
PS2Moderate
PS2 · moderate
This variant was reported as de novo in multiple affected individuals with MCAP, including parent-proband trio analysis in the original megalencephaly cohort, which supports PS2_Moderate. The stronger PS2 level was not applied because affected-tissue versus other-tissue allele-fraction data required for PS2_Strong were not established in the reviewed evidence.
PM1Supporting
PM1 · supporting
Residue Gly914 lies within the PIK3CA kinase-domain interval 797-1068 listed in Table 4 of the Brain Malformations VCEP specification, so PM1 is met at Supporting strength under the gene-specific domain rule.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the VCEP population threshold 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: PS2 moderate (+2) + PM1 supporting (+1) + PP5 supporting (+1) + PM2 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: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
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: 4 met · 4 not met · 7 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.2740G>A (p.Gly914Arg) variant has been observed in somatic cancers in COSMIC (9 occurrences) and has been reported in ClinVar with an expert panel pathogenic classification.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population controls and meeting the Brain Malformations VCEP PM2_Supporting requirement.
In a published functional study of megalencephaly-associated PI3K-pathway variants, mutant lymphoblastoid cell lines showed increased PIP3 and increased downstream S6 and 4E-BP1 phosphorylation, consistent with gain-of-function pathway activation, although an exact p.Gly914Arg-specific validated assay was not identified.
REVEL was 0.871, BayesDel was 0.382681, and SpliceAI predicted no significant splice impact with a maximum delta score of 0.13; however, this VCEP does not apply PP3 to gain-of-function missense variants.
No criteria match.
Met · 4
PS2 ModerateThis variant was reported as de novo in multiple affected individuals with MCAP, including parent-proband trio analysis in the original megalencephaly cohort, which supports PS2_Moderate. The stronger PS2 level was not applied because affected-tissue versus other-tissue allele-fraction data required for PS2_Strong were not established in the reviewed evidence. Details ▾Hide ▴
Rule
Award PS2_Moderate if criterion 1 is fulfilled, or if parents are not available but criterion 2 is fulfilled.
Evidence considered
- PMID 22729224 lists p.Gly914Arg as de novo in multiple affected individuals
- VCEP PS2_Moderate requires criterion 1 or criterion 2 when parents are unavailable
Still missing
- Affected-tissue versus other-tissue allele-fraction data were not established for PS2_Strong.
Sources
PM1 SupportingResidue Gly914 lies within the PIK3CA kinase-domain interval 797-1068 listed in Table 4 of the Brain Malformations VCEP specification, so PM1 is met at Supporting strength under the gene-specific domain rule. Details ▾Hide ▴
Rule
For PIK3CA, PM1 is Supporting for variants in approved Table 4 domains.
Evidence considered
- PIK3CA p.Gly914Arg
- Table 4 approved kinase-domain interval 797-1068
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the VCEP population threshold and supports PM2 at Supporting strength. Details ▾Hide ▴
Rule
Absent or rare from controls; for this VCEP PM2 is capped at Supporting.
Evidence considered
- gnomAD v2.1 absent
- gnomAD v4.1 absent
- VCEP PM2 is Supporting with one person maximum
Sources
PP5 SupportingExpert panel ClinGen Brain Malformations Variant Curation Expert Panel classified as Pathogenic. Details ▾Hide ▴
Not met · 4 · evaluated, threshold not reached
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its observed population frequency is 0%, which is below the VCEP BA1 threshold of greater than 0.0926%. Details ▾Hide ▴
Rule
BA1 applies when allele frequency is greater than 0.0926% for this VCEP.
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, so its observed population frequency is 0%, which is below the VCEP BS1 threshold of greater than 0.0185%. Details ▾Hide ▴
Rule
BS1 applies when allele frequency is greater than 0.0185% for this VCEP.
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, so it does not meet the VCEP BS2 threshold of at least 3 homozygotes in population data, and no well-phenotyped unaffected family carriers were identified. Details ▾Hide ▴
Rule
Award BS2 if ≥3 homozygotes are present in gnomAD or ≥3 heterozygotes are present in well-phenotyped family members.
Evidence considered
- gnomAD v2.1 absent
- gnomAD v4.1 absent
- BS2 threshold requires ≥3 homozygotes or ≥3 well-phenotyped unaffected heterozygotes
Still missing
- No family-based unaffected carrier data were identified.
Sources
BS3 No well-established study showed normal function for p.Gly914Arg. Available published pathway assays instead showed increased PI3K-pathway signaling in megalencephaly-associated PIK3CA or PIK3R2 mutant cell lines, which does not support BS3. Details ▾Hide ▴
Rule
BS3 requires well-established functional studies showing no damaging effect on protein function or splicing.
Evidence considered
- Published pathway assays showed increased PIP3 and downstream signaling in related mutant lines
- No normal-function assay for p.Gly914Arg identified
Still missing
- Need an exact variant-specific
- well-validated assay demonstrating no damaging effect if BS3 is to be considered.
Sources
Not assessed · 7 · no assessment recorded
PS1 No previously established pathogenic alternate nucleotide change producing the same p.Gly914Arg amino acid substitution was identified in the reviewed evidence, so PS1 was not assessed. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Evidence considered
- ClinVar record reviewed for this amino acid change.
Still missing
- Need confirmation whether another nucleotide change causing p.Gly914Arg has an established pathogenic classification under this framework.
Sources
PS3 Published cell-based studies showed increased PI3K-pathway signaling in megalencephaly-associated mutant lines, but an exact p.Gly914Arg-specific validated functional assay meeting the VCEP PS3 requirements was not identified. In addition, the VCEP states that patient-derived cells alone are insufficient for strong PS3 evidence. Details ▾Hide ▴
Rule
Apply only when functional assay evidence meets SVI and VCEP quality requirements.
Evidence considered
- Published pathway assays in related mutant lines
- VCEP caveat excluding patient-derived cells alone from strong PS3
Still missing
- Need an exact variant-specific
- well-validated functional assay meeting VCEP/SVI requirements if PS3 is to be applied.
Sources
PS4 This variant was reported in at least five affected individuals with MCAP and is absent from gnomAD v2.1 and v4.1, so case enrichment evidence is present. However, the exact Table 2A phenotype point total needed to assign a PS4 strength under this VCEP was not directly recoverable from the reviewed materials, so PS4 was left for manual point-based adjudication. Details ▾Hide ▴
Rule
Points are assigned by phenotype category in Table 2A and converted to PS4 strength by Table 2B; PM2 is required first.
Evidence considered
- PMID 22729224 reports at least five MCAP cases with p.Gly914Arg
- gnomAD v2.1 absent
- gnomAD v4.1 absent
- VCEP PS4 requires Table 2A/Table 2B point calculation after PM2
Still missing
- Need Table 2A phenotype point assignment for each reported case to calculate the total PS4 score.
Sources
PM5 No different established pathogenic missense change at codon Gly914 was identified in the reviewed evidence, so PM5 was not assessed. Details ▾Hide ▴
Rule
Novel missense change at an amino acid residue where a different pathogenic missense change has been seen before.
Evidence considered
- ClinVar record for the exact variant reviewed
Still missing
- Need confirmation of another established pathogenic missense substitution at the same codon under this framework.
Sources
PP2 This VCEP allows PP2 for PIK3CA missense variants when the missense constraint z-score is greater than 3.09, but that gene-level constraint value was not provided in the reviewed materials. Details ▾Hide ▴
Rule
Award PP2 if the missense constraint z-score is >3.09.
Evidence considered
- PP2 rule requires missense constraint z-score >3.09
Still missing
- Need the applicable missense constraint z-score to determine whether PP2 can be applied.
Sources
BP2 No cis or trans observation with another established pathogenic PIK3CA variant was identified, so BP2 was not assessed. Details ▾Hide ▴
Rule
Observed in cis or trans with a known pathogenic variant in the same gene.
Evidence considered
- No phasing evidence identified
Still missing
- Need phase information showing this variant in cis or trans with a known pathogenic PIK3CA variant.
Sources
BP5 No alternate molecular diagnosis explaining the phenotype was identified in the reviewed evidence, so BP5 was not assessed. Details ▾Hide ▴
Rule
Variant found in a case with an alternate molecular basis for disease.
Evidence considered
- No alternate molecular basis reported in reviewed materials
Still missing
- Need case-specific evidence of an alternate molecular basis for disease if BP5 is to be considered.
Sources
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable in this VCEP because the disease mechanism for PIK3CA-related brain malformations is gain of function, and this missense variant is not a null variant category in the generic PVS1 framework. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
- Brain Malformations VCEP states PVS1 is not applicable for PIK3CA
- Variant is a missense substitution
- not a canonical PVS1 null variant
Sources
cspec ↗pvs1_variant_assessment
PM3 N/APM3 is not applicable in this VCEP. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
- Brain Malformations VCEP applicability statement for PM3.
Sources
PM4 N/APM4 is not applicable in this VCEP. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
- Brain Malformations VCEP applicability statement for PM4.
Sources
PM6 N/APM6 is not applicable in this VCEP. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
- Brain Malformations VCEP applicability statement for PM6.
Sources
PP1 N/APP1 is not applicable in this VCEP. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
- Brain Malformations VCEP applicability statement for PP1.
Sources
PP3 N/APP3 is not applicable in this VCEP for gain-of-function disorders. REVEL was 0.871, BayesDel was 0.382681, and SpliceAI predicted no significant splice effect with a maximum delta score of 0.13, but these scores are not used for PP3 under this gene-specific framework. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
- REVEL 0.871
- BayesDel 0.382681
- SpliceAI max delta 0.13
- VCEP states PP3 is not applicable for GOF variants
Sources
PP4 N/APP4 is not applicable in this VCEP because phenotype specificity is incorporated into PS4. Details ▾Hide ▴
Rule
Not applicable since this criterion is accounted for under PS4.
Evidence considered
- Brain Malformations VCEP applicability statement for PP4.
Sources
BS4 N/ABS4 is not applicable in this VCEP because these disorders are typically de novo, germline mosaic, or post-zygotic. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
- Brain Malformations VCEP applicability statement for BS4.
Sources
BP1 N/ABP1 is not applicable in this VCEP because the disease mechanism is gain of function rather than truncating loss of function. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
- Brain Malformations VCEP applicability statement for BP1.
Sources
BP3 N/ABP3 is not applicable in this VCEP. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
- Brain Malformations VCEP applicability statement for BP3.
Sources
BP4 N/ABP4 is not applicable in this VCEP for missense variants. SpliceAI predicted no significant splice effect with a maximum delta score of 0.13, but the VCEP limits BP4 to synonymous, intronic, and certain non-coding variants. Details ▾Hide ▴
Rule
Not applicable for missense variants in this VCEP framework.
Evidence considered
- SpliceAI max delta 0.13
- VCEP BP4 applicability is restricted to non-missense variants
Sources
BP6 N/ABP6 is not applicable in this VCEP. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
- Brain Malformations VCEP applicability statement for BP6.
Sources
BP7 N/ABP7 is not applicable because this is a missense variant rather than a synonymous, intronic, or UTR variant. Details ▾Hide ▴
Rule
BP7 is for synonymous, intronic, and certain non-coding variants only.
Evidence considered
- Variant is missense p.Gly914Arg
Sources
Identifiers
- Gene
- PIK3CA
- Transcript
- NM_006218.2
- Coding (HGVS c.)
- NM_006218.2:c.2740G>A
- Protein (HGVS p.)
- NP_006209.2:p.(Gly914Arg)
- GRCh38
- chr3:179230077 G>A
- GRCh37
- chr3:178947865 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 in this VCEP for gain-of-function disorders. REVEL was 0.871, BayesDel was 0.382681, and SpliceAI predicted no significant splice effect with a maximum delta score of 0.13, but these scores are not used for PP3 under this gene-specific framework. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
- REVEL 0.871
- BayesDel 0.382681
- SpliceAI max delta 0.13
- VCEP states PP3 is not applicable for GOF variants
Sources
BP4 N/ABP4 is not applicable in this VCEP for missense variants. SpliceAI predicted no significant splice effect with a maximum delta score of 0.13, but the VCEP limits BP4 to synonymous, intronic, and certain non-coding variants. Details ▾Hide ▴
Rule
Not applicable for missense variants in this VCEP framework.
Evidence considered
- SpliceAI max delta 0.13
- VCEP BP4 applicability is restricted to non-missense variants
Sources
BP7 N/ABP7 is not applicable because this is a missense variant rather than a synonymous, intronic, or UTR variant. Details ▾Hide ▴
Rule
BP7 is for synonymous, intronic, and certain non-coding variants only.
Evidence considered
- Variant is missense p.Gly914Arg
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.13). REVEL score = 0.871. BayesDel score = 0.382681.
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/39703/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-178947865-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-179230077-G-A?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006218.2%3Ac.2740…
- OncoKB ↗www.oncokb.org/gene/PIK3CA/G914R
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=108169627
- 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 (13 clinical laboratories) and as Likely pathogenic (3 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 = 0.13). REVEL score = 0.871. BayesDel score = 0.382681.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55930478, n = 9 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.