About PIK3CA
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PIK3CA c.397G>A, p.(Asp133Asn)
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. 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 (exomes) and gnomAD v4.1 (exomes/genomes). Under the BMVCEP, PM2 is awarded at supporting strength for variants absent or rare (≤1) in population controls.
PP2Supporting
PP2 · supporting
PIK3CA has a high gnomAD missense constraint z-score well above the BMVCEP threshold of 3.09, indicating a low rate of benign missense variation. This variant is a missense change in a gene where missense variants are a common disease mechanism. PP2 applies specifically to PIK3CA, MTOR, and AKT3 per the VCEP.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
ClinGen Brain Malformations Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.1 v1.1 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, PP2 supporting; combination = 2 supporting, 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.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.060 maximum delta
Recorded SpliceAI maximum delta score: 0.060. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PIK3CA, the catalytic subunit of PI3-kinase, is frequently mutated in a diverse range of cancers including breast, endometrial and cervical cancers.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
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, with the data and sources behind each one.
26 criteria with recorded statuses: 2 met · 12 not met · 0 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_006218.4:c.397G>A (p.Asp133Asn) in PIK3CA is absent from gnomAD population databases (v2.1, v4.1), meeting PM2 at supporting strength per the ClinGen Brain Malformations VCEP v1.1.
PIK3CA has a high missense constraint z-score exceeding the BMVCEP threshold of 3.09, consistent with a gene where missense variants are a common disease mechanism, meeting PP2 at supporting strength.
PVS1 is not applicable because the disease mechanism for PIK3CA-related brain malformations is gain of function, as specified by the BMVCEP v1.1.
Residue Asp133 falls outside all Table 4 approved functional domains for PIK3CA (ABD 31-108, Ras-binding 173-292, kinase 322-483, kinase 797-1068); PM1 is not met.
No functional data, no de novo reports, no phenotype cases, no ClinVar entries, and no literature citations were identified for this variant. PS1, PS2, PS3, PS4, and PM5 are not met.
Applying the BMVCEP Tavtigian point framework (PMID:32720330): PM2_Supporting (+1) + PP2_Supporting (+1) = 2 points total. Score of 2 falls within the VUS range (0-5).
No benign criteria are met: BA1 and BS1 population frequency thresholds are not exceeded; BS2 requires homozygotes or well-phenotyped heterozygotes not observed; BS3 lacks functional studies showing no effect; BP2, BP5 lack supporting evidence.
No criteria match.
Met · 2
PM2 SupportingThis variant is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (exomes/genomes). Under the BMVCEP, PM2 is awarded at supporting strength for variants absent or rare (≤1) in population controls. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 and v4.1 population databases.
Sources
PP2 SupportingPIK3CA has a high gnomAD missense constraint z-score well above the BMVCEP threshold of 3.09, indicating a low rate of benign missense variation. This variant is a missense change in a gene where missense variants are a common disease mechanism. PP2 applies specifically to PIK3CA, MTOR, and AKT3 per the VCEP. Details ▾Hide ▴
Evidence considered
- PIK3CA missense z-score exceeds 3.09 threshold in gnomAD
- consistent with significant missense constraint. BMVCEP explicitly names PIK3CA as eligible for PP2.
Sources
Not met · 12 · evaluated, threshold not reached
PS1 No same amino acid change has been previously established as pathogenic per BMVCEP criteria independent of this point. The variant (p.Asp133Asn) is absent from ClinVar and no prior pathogenic classification at this residue was identified. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no pathogenic comparator at the same amino acid position.
Still missing
- No prior pathogenic assertion at residue Asp133.
Sources
PS2 No de novo occurrence data is available for this variant. The BMVCEP requires confirmed maternity and paternity with variant absent from parents (Criteria 1) and presence in affected tissue with lower/absent allelic fraction in another tissue (Criteria 2) for PS2_Strong, or at least one criterion for PS2_Moderate. Neither criterion is met from available evidence. Details ▾Hide ▴
Evidence considered
- No de novo or tissue-specific allelic fraction data identified for this variant.
Still missing
- No parental testing or tissue mosaicism data available.
Sources
PS3 No functional assay data is available for this specific variant (p.Asp133Asn). OncoKB reports Unknown Oncogenic Effect with no variant-specific reviewed functional evidence. No PMIDs were identified from literature screening. The BMVCEP requires functional assays meeting SVI quality metrics and validation controls (PMID:31892348), which are not available for this variant. Details ▾Hide ▴
Evidence considered
- OncoKB reports Unknown Oncogenic Effect. No variant-specific functional studies identified in literature screening.
Still missing
- No functional assay data for p.Asp133Asn.
Sources
PS4 PS4 requires PM2 first (which is met) and phenotype points per Table 2A/2B of the BMVCEP. No proband phenotype data, no literature cases, no ClinVar submissions, and no COSMIC entries were identified for this variant. Total points = 0, which is below the PS4_Supporting threshold of 0.5 points. Details ▾Hide ▴
PM1 Residue Asp133 falls outside all approved Table 4 functional domains for PIK3CA. The approved domains are: adaptor binding domain (AA 31-108), kinase Ras-binding domain (AA 173-292), and kinase domains (AA 322-483 and AA 797-1068). Position 133 lies between the ABD and Ras-binding domains and is not within any Table 4 domain. Cancer Hotspots analysis also found no statistically significant hotspot at this residue. Details ▾Hide ▴
Evidence considered
- Residue D133 is outside all Table 4 PIK3CA domains (ABD 31-108
- Ras-binding 173-292
- kinase 322-483
- kinase 797-1068). Not a significant hotspot per cancerhotspots.org.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
PM5 No pathogenic missense variants have been established at residue Asp133. The BMVCEP requires that the comparator variant be established as pathogenic per BMVCEP criteria independent of this point. No same-residue ClinVar candidates were identified for this residue. Details ▾Hide ▴
Evidence considered
- No same-residue (Asp133) pathogenic missense comparator variants identified in ClinVar or literature.
Still missing
- No established pathogenic missense change at residue Asp133.
Sources
pm5_candidatesclinvar ↗
BA1 This variant is absent from gnomAD v2.1 and v4.1 (allele frequency 0%). The BMVCEP BA1 threshold is allele frequency > 0.0926%. Details ▾Hide ▴
Evidence considered
- Variant absent from gnomAD (AF 0%). Does not exceed BA1 threshold of >0.0926%.
Sources
BS1 This variant is absent from gnomAD v2.1 and v4.1 (allele frequency 0%). The BMVCEP BS1 threshold is allele frequency > 0.0185%. Details ▾Hide ▴
Evidence considered
- Variant absent from gnomAD (AF 0%). Does not exceed BS1 threshold of >0.0185%.
Sources
BS2 No homozygotes are present in gnomAD for this variant, and no well-phenotyped heterozygous family members have been identified. The BMVCEP requires ≥3 homozygotes in gnomAD or ≥3 heterozygous well-phenotyped family members for BS2. Details ▾Hide ▴
Evidence considered
- Variant absent from gnomAD. No homozygous occurrences and no well-phenotyped heterozygous family members identified.
Still missing
- No homozygous or well-phenotyped heterozygous observations.
Sources
BS3 No well-established in vitro or in vivo functional studies show no damaging effect on protein function for this variant. No functional assay data was identified for p.Asp133Asn. The BMVCEP requires functional studies meeting SVI quality metrics and validation controls (PMID:31892348). Details ▾Hide ▴
Evidence considered
- No functional assay data identified for p.Asp133Asn. OncoKB reports Unknown Oncogenic Effect.
Still missing
- No functional studies showing no damaging effect on protein function.
Sources
BP2 No evidence that this variant has been observed in cis or trans with a known pathogenic variant in PIK3CA. Details ▾Hide ▴
Evidence considered
- No phasing data available
- variant not observed with a known pathogenic variant in PIK3CA.
Still missing
- No cis/trans phase information with pathogenic PIK3CA variants.
BP5 No evidence that this variant has been found in a case with an alternate molecular basis for disease in a different gene. Details ▾Hide ▴
Evidence considered
- No alternate molecular basis for disease identified in available evidence.
Still missing
- No data on alternate molecular diagnoses in carriers of this variant.
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 VCEPNot applicable under the ClinGen Brain Malformations VCEP v1.1. The disease mechanism for PIK3CA is gain of function (GOF); loss of function and/or haploinsufficiency have not been clearly identified as disease mechanisms underlying brain malformations related to these genes. Details ▾Hide ▴
Evidence considered
- VCEP specification states PVS1 is not applicable because disease mechanism is gain of function.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
PM6 VCEPNot applicable under the BMVCEP v1.1. This point is addressed according to PS2 and will not be used separately. Details ▾Hide ▴
Evidence considered
- VCEP specification states PM6 is addressed by PS2 and will not be used.
Sources
PP1 VCEPNot applicable under the BMVCEP v1.1. Disease-causing variants are germline mosaic, de novo, or mosaic, making co-segregation analysis inapplicable. Details ▾Hide ▴
Evidence considered
- VCEP specification states PP1 is not applicable since disease-causing variants are germline mosaic
- de novo
- or mosaic.
Sources
PP3 VCEPNot applicable under the BMVCEP v1.1. These variants are gain of function, and traditional mutation pathogenicity prediction algorithms focus on loss of function mechanisms. Use may be revisited if algorithms specifically designed to detect GOF mutations emerge. Details ▾Hide ▴
Evidence considered
- VCEP specification states PP3 is not applicable since variants are GOF and traditional prediction algorithms focus on LOF mechanisms.
Sources
PP4 VCEPNot applicable under the BMVCEP v1.1. This criterion is accounted for under PS4. Details ▾Hide ▴
PP5 VCEPNot applicable under the BMVCEP v1.1. This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
Evidence considered
- VCEP specification states PP5 is not for use per ClinGen SVI VCEP Review Committee.
Sources
BS4 VCEPNot applicable under the BMVCEP v1.1. These are de novo, germline mosaic, or post-zygotic mutations, making segregation analysis inapplicable. Details ▾Hide ▴
Evidence considered
- VCEP specification states BS4 is not applicable as these are de novo
- germline mosaic or post-zygotic mutations.
Sources
BP1 VCEPNot applicable under the BMVCEP v1.1. Loss of function is not the disease mechanism for PIK3CA-related brain malformations; the mechanism is gain of function. Details ▾Hide ▴
Evidence considered
- VCEP specification states BP1 is not applicable as LOF is not the disease mechanism.
Sources
BP4 N/ANot applicable for this variant type under the BMVCEP v1.1. BP4 is restricted to synonymous, intronic (except canonical splice sites), and non-coding variants in UTRs, assessed by two of three splicing prediction tools (varSEAK, SpliceAI, MaxEntScan) predicting no splicing change. This is a missense variant. Details ▾Hide ▴
Evidence considered
- BP4 restricted to synonymous
- intronic
- and UTR variants only per VCEP specification. This is a missense variant.
Sources
BP6 VCEPNot applicable under the BMVCEP v1.1. This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
Evidence considered
- VCEP specification states BP6 is not for use per ClinGen SVI VCEP Review Committee.
Sources
BP7 N/ANot applicable for this variant type under the BMVCEP v1.1. BP7 is restricted to synonymous, intronic (except canonical splice sites), and non-coding variants in UTRs, assessed by nucleotide conservation (PhyloP score < 0.1). This is a missense variant (c.397G>A, p.Asp133Asn). Details ▾Hide ▴
Evidence considered
- BP7 restricted to synonymous
- intronic
- and UTR variants only per VCEP specification. This is a missense variant.
Sources
PS5 N/APS5 is not a recognized ACMG/AMP criterion and is not part of the ClinGen Brain Malformations VCEP v1.1 framework. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- PIK3CA
- Transcript
- NM_006218.4
- Coding (HGVS c.)
- NM_006218.4:c.397G>A
- Protein (HGVS p.)
- NP_006209.2:p.(Asp133Asn)
- GRCh38
- chr3:179199734 G>A
- GRCh37
- chr3:178917522 G>A
Gene diagram
Every interpreted variant in PIK3CA, mapped onto the exon structure of NM_006218.4. Select a row to find it on the plot.
PIK3CANM_006218.4
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
- 0.190
- BayesDel
- -0.494
How the predictions were used
PP3 VCEPNot applicable under the BMVCEP v1.1. These variants are gain of function, and traditional mutation pathogenicity prediction algorithms focus on loss of function mechanisms. Use may be revisited if algorithms specifically designed to detect GOF mutations emerge. Details ▾Hide ▴
Evidence considered
- VCEP specification states PP3 is not applicable since variants are GOF and traditional prediction algorithms focus on LOF mechanisms.
Sources
BP4 N/ANot applicable for this variant type under the BMVCEP v1.1. BP4 is restricted to synonymous, intronic (except canonical splice sites), and non-coding variants in UTRs, assessed by two of three splicing prediction tools (varSEAK, SpliceAI, MaxEntScan) predicting no splicing change. This is a missense variant. Details ▾Hide ▴
Evidence considered
- BP4 restricted to synonymous
- intronic
- and UTR variants only per VCEP specification. This is a missense variant.
Sources
BP7 N/ANot applicable for this variant type under the BMVCEP v1.1. BP7 is restricted to synonymous, intronic (except canonical splice sites), and non-coding variants in UTRs, assessed by nucleotide conservation (PhyloP score < 0.1). This is a missense variant (c.397G>A, p.Asp133Asn). Details ▾Hide ▴
Evidence considered
- BP7 restricted to synonymous
- intronic
- and UTR variants only per VCEP specification. This is a missense variant.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06). REVEL score = 0.19. BayesDel score = -0.494007.
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
Recorded maximum delta 0.060
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/?term=NM_006218.4%3Ac.397G%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-178917522-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-179199734-G-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/3-179199734-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006218.4%3Ac.397G…
- OncoKB ↗www.oncokb.org/gene/PIK3CA/D133N
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PIK3CA+c.397G%3EA
- 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 is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06). REVEL score = 0.19. BayesDel score = -0.494007.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PIK3CA, the catalytic subunit of PI3-kinase, is frequently mutated in a diverse range of cancers including breast, endometrial and cervical cancers.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.