About PIK3CA
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PIK3CA c.93A>G, p.(Ile31Met)
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 consistent with the Brain Malformations VCEP PM2 rule for variants absent or rare in controls. Under this VCEP, PM2 is capped at supporting strength, so PM2 is met at supporting strength.
PP2Supporting
PP2 · supporting
The Brain Malformations VCEP allows PP2 for PIK3CA missense variants when the missense constraint z-score is greater than 3.09. Live gnomAD constraint review identified a PIK3CA missense z-score of 5.60, which is above this threshold, so PP2 is met at supporting strength.
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: PP2 supporting (+1) + PM2 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.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Neutral; curated oncogenicity label: Likely Neutral.
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 does not lie 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 · 10 not met · 2 not assessed · 14 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.93A>G (p.Ile31Met) variant has been observed in somatic cancers in COSMIC (COSV55898376, n=2) and has been reported in ClinVar as Uncertain Significance by the ClinGen Brain Malformations Variant Curation Expert Panel.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population databases and meeting PM2 at supporting strength under the Brain Malformations VCEP framework.
The missense change affects codon 31, which is outside the PIK3CA Table 4 kinase-domain intervals used for PM1 and was not identified as a statistically significant hotspot in the retrieved hotspot review.
Computational review showed REVEL 0.286, BayesDel -0.0727233, and SpliceAI max delta 0.06, but the Brain Malformations VCEP does not apply PP3 to PIK3CA gain-of-function missense variants and restricts BP4 to synonymous, intronic, or UTR variants.
No criteria match.
Met · 2
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1, which is consistent with the Brain Malformations VCEP PM2 rule for variants absent or rare in controls. Under this VCEP, PM2 is capped at supporting strength, so PM2 is met at supporting strength. Details ▾Hide ▴
Rule
Brain Malformations VCEP PM2_Supporting for absent/rare in controls.
Evidence considered
- Variant absent from gnomAD v2.1.
- Variant absent from gnomAD v4.1.
Sources
PP2 SupportingThe Brain Malformations VCEP allows PP2 for PIK3CA missense variants when the missense constraint z-score is greater than 3.09. Live gnomAD constraint review identified a PIK3CA missense z-score of 5.60, which is above this threshold, so PP2 is met at supporting strength. Details ▾Hide ▴
Rule
Brain Malformations VCEP PP2_Supporting if missense z-score >3.09.
Evidence considered
- PIK3CA missense z-score 5.5986 from gnomAD constraint data.
- VCEP PP2 threshold >3.09.
Still missing
- A case-registered gene-constraint source would improve traceability in the downstream packet.
Sources
Not met · 10 · evaluated, threshold not reached
PS1 No previously established pathogenic PIK3CA variant with the same amino acid change at p.Ile31 was identified. Other ClinVar missense substitutions at codon 31 identified in the reviewed evidence are classified as uncertain significance rather than pathogenic, so PS1 is not met. Details ▾Hide ▴
Rule
Brain Malformations VCEP PS1: same amino acid change as a previously established pathogenic variant.
Evidence considered
- ClinVar lists p.Ile31Met as uncertain significance and nearby codon 31 substitutions identified from ClinVar are not established pathogenic variants.
Still missing
- Direct confirmation of any newly submitted same-amino-acid pathogenic assertions would be needed if additional data emerge.
Sources
PS2 No report was identified showing this variant was absent from confirmed parental samples, and no tissue-comparison evidence was identified showing a higher allele fraction in affected tissue than in another tissue. Therefore the VCEP requirements for PS2 are not met. Details ▾Hide ▴
Rule
Brain Malformations VCEP PS2_Strong or PS2_Moderate for confirmed de novo or informative tissue mosaicism.
Evidence considered
- Brain Malformations VCEP PS2 requires parental absence and/or informative tissue-level mosaic data.
Still missing
- No confirmed maternity/paternity de novo report was identified.
- No mosaic tissue-comparison data were identified for this exact variant.
Sources
PS4 Although PM2 is met, no report-ready affected-individual phenotype point assignments were identified for this variant under the Brain Malformations VCEP PS4 framework. Two somatic observations in COSMIC do not establish the minimum case-based evidence needed to reach PS4_Supporting, so PS4 is not met. Details ▾Hide ▴
Rule
Brain Malformations VCEP PS4 point-based framework requiring PM2 first.
Evidence considered
- Variant absent from gnomAD v2.1 and v4.1
- satisfying PM2.
- COSMIC reports 2 somatic observations.
Still missing
- No constitutional or mosaic disease cases with assignable Table 2A phenotype points were identified.
- Independent affected-case reports would be needed to score PS4.
Sources
PM1 The p.Ile31Met change is outside the PIK3CA Table 4 critical domains approved for PM1 under this VCEP, which are amino acids 322-483 and 797-1068. The retrieved hotspot review also did not show a statistically significant hotspot at codon 31, so PM1 is not met. Details ▾Hide ▴
Rule
Brain Malformations VCEP PM1_Supporting only for Table 4 approved domains.
Evidence considered
- PIK3CA PM1-approved domains are aa 322-483 and aa 797-1068.
- Cancer Hotspots review did not identify a significant hotspot at residue I31.
Still missing
- Additional codon-specific functional-domain evidence would be needed to reconsider PM1.
Sources
PM5 No different missense change at codon 31 was identified as an established pathogenic PIK3CA variant in the reviewed evidence. Other codon 31 ClinVar substitutions identified in the review are classified as uncertain significance, so PM5 is not met. Details ▾Hide ▴
Rule
Brain Malformations VCEP PM5: novel missense change at an amino acid residue where a different pathogenic missense change has been seen.
Evidence considered
- ClinVar codon 31 substitutions identified in the review are not established pathogenic variants.
Still missing
- Direct confirmation of any newly established pathogenic codon 31 variants would be needed if future submissions appear.
Sources
BA1 This variant was absent from gnomAD v2.1 and gnomAD v4.1, which is below the Brain Malformations VCEP BA1 threshold of greater than 0.0926%. Therefore BA1 is not met. Details ▾Hide ▴
Rule
Brain Malformations VCEP BA1: allele frequency >0.0926%.
Evidence considered
- Variant absent from gnomAD v2.1.
- Variant absent from gnomAD v4.1.
Sources
BS1 This variant was absent from gnomAD v2.1 and gnomAD v4.1, which is below the Brain Malformations VCEP BS1 threshold of greater than 0.0185%. Therefore BS1 is not met. Details ▾Hide ▴
Rule
Brain Malformations VCEP BS1: allele frequency >0.0185%.
Evidence considered
- Variant absent from gnomAD v2.1.
- Variant absent from gnomAD v4.1.
Sources
BS2 The reviewed evidence does not show at least 3 homozygotes in gnomAD or at least 3 well-phenotyped unaffected heterozygous family members, so BS2 is not met. Details ▾Hide ▴
Rule
Brain Malformations VCEP BS2: at least 3 homozygotes in gnomAD or at least 3 well-phenotyped unaffected heterozygous family members.
Evidence considered
- Variant absent from gnomAD v2.1.
- Variant absent from gnomAD v4.1.
Still missing
- Well-phenotyped family data were not identified.
- No homozygous population observations were identified.
Sources
BP2 No evidence was identified showing this variant in cis or in trans with a known pathogenic PIK3CA variant, so BP2 is not met. Details ▾Hide ▴
Rule
Brain Malformations VCEP BP2: observed in cis or trans with a known pathogenic variant in the same gene.
Evidence considered
- No cis/trans observation with a pathogenic PIK3CA variant was documented.
Still missing
- Phase data were not identified.
Sources
BP5 No alternate molecular basis for the phenotype was identified in the reviewed evidence, so BP5 is not met. Details ▾Hide ▴
Rule
Brain Malformations VCEP BP5: alternate molecular basis for disease.
Evidence considered
- No alternate disease-causing finding was documented in the reviewed evidence.
Still missing
- Case-level molecular differential data were not provided.
Sources
Not assessed · 2 · no assessment recorded
PS3 Curated literature links for possible functional review were identified, but no independently confirmed exact-variant validated functional study showing an abnormal gain-of-function effect was established from the reviewed evidence. Therefore PS3 was not assessed. Details ▾Hide ▴
Rule
Brain Malformations VCEP PS3 requires validated functional evidence supporting a pathogenic effect.
Evidence considered
- OncoKB linked candidate functional PMIDs 26627007
- 28528867
- and 29533785.
Still missing
- Direct review of an exact-variant validated functional study meeting VCEP quality requirements would be needed.
Sources
BS3 Curated literature links for possible functional review were identified, but no independently confirmed exact-variant functional study showing a normal or benign effect was established from the reviewed evidence. Therefore BS3 was not assessed. Details ▾Hide ▴
Rule
Brain Malformations VCEP BS3 requires validated functional evidence supporting a benign effect.
Evidence considered
- OncoKB linked candidate functional PMIDs 26627007
- 28528867
- and 29533785.
Still missing
- Direct review of an exact-variant validated functional study showing no gain-of-function effect would be needed.
Sources
Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable for PIK3CA in this Brain Malformations VCEP framework because the relevant disease mechanism is gain of function rather than loss of function. This missense variant also does not fall into a generic null-variant category. Details ▾Hide ▴
Rule
Brain Malformations VCEP: PVS1 not applicable for GOF genes.
Evidence considered
- Brain Malformations VCEP states PVS1 is not applicable for PIK3CA.
- Variant-level PVS1 scaffold classifies this change outside the default null-variant buckets.
Sources
cspec ↗pvs1_variant_assessment
PM3 N/APM3 is not applicable in this Brain Malformations VCEP framework. Details ▾Hide ▴
Rule
Brain Malformations VCEP: PM3 not applicable.
Evidence considered
- Brain Malformations VCEP marks PM3 as not applicable.
Sources
PM4 N/APM4 is not applicable in this Brain Malformations VCEP framework. Details ▾Hide ▴
Rule
Brain Malformations VCEP: PM4 not applicable.
Evidence considered
- Brain Malformations VCEP marks PM4 as not applicable.
Sources
PM6 N/APM6 is not applicable in this Brain Malformations VCEP framework. Details ▾Hide ▴
Rule
Brain Malformations VCEP: PM6 not applicable.
Evidence considered
- Brain Malformations VCEP marks PM6 as not applicable.
Sources
PP1 N/APP1 is not applicable in this Brain Malformations VCEP framework. Details ▾Hide ▴
Rule
Brain Malformations VCEP: PP1 not applicable.
Evidence considered
- Brain Malformations VCEP marks PP1 as not applicable.
Sources
PP3 N/AComputational review showed REVEL 0.286, BayesDel -0.0727233, and SpliceAI max delta 0.06, but the Brain Malformations VCEP does not apply PP3 to PIK3CA gain-of-function variants because traditional pathogenicity predictors are not considered reliable for this mechanism. Details ▾Hide ▴
Rule
Brain Malformations VCEP: PP3 not applicable for GOF variants.
Evidence considered
- REVEL 0.286.
- BayesDel -0.0727233.
- SpliceAI max delta 0.06.
Sources
PP4 N/APP4 is not applicable in this Brain Malformations VCEP framework because phenotype specificity is incorporated into the PS4 point-based system. Details ▾Hide ▴
Rule
Brain Malformations VCEP: PP4 not applicable.
Evidence considered
- Brain Malformations VCEP marks PP4 as not applicable.
Sources
PP5 N/APP5 is not used in this Brain Malformations VCEP framework. Details ▾Hide ▴
Rule
Brain Malformations VCEP: PP5 not applicable.
Evidence considered
- Brain Malformations VCEP marks PP5 as not applicable.
Sources
BS4 N/ABS4 is not applicable in this Brain Malformations VCEP framework because these disorders are typically caused by de novo, germline mosaic, or post-zygotic variants rather than informative multi-generation segregation patterns. Details ▾Hide ▴
Rule
Brain Malformations VCEP: BS4 not applicable.
Evidence considered
- Brain Malformations VCEP marks BS4 as not applicable.
Sources
BP1 N/ABP1 is not applicable for PIK3CA in this Brain Malformations VCEP framework because the disease mechanism is gain of function rather than the pattern addressed by BP1. Details ▾Hide ▴
Rule
Brain Malformations VCEP: BP1 not applicable.
Evidence considered
- Brain Malformations VCEP marks BP1 as not applicable.
Sources
BP3 N/ABP3 is not applicable in this Brain Malformations VCEP framework. Details ▾Hide ▴
Rule
Brain Malformations VCEP: BP3 not applicable.
Evidence considered
- Brain Malformations VCEP marks BP3 as not applicable.
Sources
BP4 N/ASpliceAI predicts no significant splice impact with a maximum delta score of 0.06, but this Brain Malformations VCEP applies BP4 only to synonymous, intronic, or UTR variants evaluated for splicing. Because this is a missense variant, BP4 is not applicable. Details ▾Hide ▴
Rule
Brain Malformations VCEP BP4 restricted to synonymous/intronic/UTR variants for splicing prediction.
Evidence considered
- SpliceAI max delta 0.06.
- Variant is missense p.Ile31Met.
Sources
BP6 N/ABP6 is not applicable in this Brain Malformations VCEP framework. Details ▾Hide ▴
Rule
Brain Malformations VCEP: BP6 not applicable.
Evidence considered
- Brain Malformations VCEP marks BP6 as not applicable.
Sources
BP7 N/ABP7 is restricted to synonymous, intronic, or certain non-coding variants, and this is a missense variant. Therefore BP7 is not applicable. Details ▾Hide ▴
Rule
Brain Malformations VCEP BP7 for synonymous/intronic/UTR variants only.
Evidence considered
- Variant is missense p.Ile31Met.
Sources
Identifiers
- Gene
- PIK3CA
- Transcript
- NM_006218.2
- Coding (HGVS c.)
- NM_006218.2:c.93A>G
- Protein (HGVS p.)
- NP_006209.2:p.(Ile31Met)
- GRCh38
- chr3:179198918 A>G
- GRCh37
- chr3:178916706 A>G
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/AComputational review showed REVEL 0.286, BayesDel -0.0727233, and SpliceAI max delta 0.06, but the Brain Malformations VCEP does not apply PP3 to PIK3CA gain-of-function variants because traditional pathogenicity predictors are not considered reliable for this mechanism. Details ▾Hide ▴
Rule
Brain Malformations VCEP: PP3 not applicable for GOF variants.
Evidence considered
- REVEL 0.286.
- BayesDel -0.0727233.
- SpliceAI max delta 0.06.
Sources
BP4 N/ASpliceAI predicts no significant splice impact with a maximum delta score of 0.06, but this Brain Malformations VCEP applies BP4 only to synonymous, intronic, or UTR variants evaluated for splicing. Because this is a missense variant, BP4 is not applicable. Details ▾Hide ▴
Rule
Brain Malformations VCEP BP4 restricted to synonymous/intronic/UTR variants for splicing prediction.
Evidence considered
- SpliceAI max delta 0.06.
- Variant is missense p.Ile31Met.
Sources
BP7 N/ABP7 is restricted to synonymous, intronic, or certain non-coding variants, and this is a missense variant. Therefore BP7 is not applicable. Details ▾Hide ▴
Rule
Brain Malformations VCEP BP7 for synonymous/intronic/UTR variants only.
Evidence considered
- Variant is missense p.Ile31Met.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06). REVEL score = 0.286. BayesDel score = -0.0727233.
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/1296992/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-178916706-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-179198918-A-G?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006218.2%3Ac.93A%…
- OncoKB ↗www.oncokb.org/gene/PIK3CA/I31M
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=108150697
- 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 Uncertain Significance by ClinGen Brain Malformations Variant Curation Expert Panel (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06). REVEL score = 0.286. BayesDel score = -0.0727233.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Neutral; curated oncogenicity label: Likely Neutral.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55898376, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.