About PIK3CA
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PIK3CA c.2198A>G, p.(Lys733Arg)
Classification
Benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.
Benign.A benign 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: 0
Benign evidence criteria: 3
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 3
BA1Stand alone
BA1 · stand alone
This variant exceeds the Brain Malformations VCEP BA1 threshold of 0.0926%. The highest observed population frequency is East Asian AF 0.56428% in gnomAD v2.1 and 0.25756% in gnomAD v4.1, both above the BA1 threshold.
BS1Strong
BS1 · strong
This variant exceeds the Brain Malformations VCEP BS1 threshold of 0.0185%. The highest observed population frequency is East Asian AF 0.56428% in gnomAD v2.1 and 0.25756% in gnomAD v4.1, both above the BS1 threshold.
BP6Supporting
BP6 · supporting
Expert panel ClinGen Brain Malformations Variant Curation Expert Panel classified as Benign.
Recorded classification: Benign
Brain Malformations Specification Tavtigian point framework v1.1.0 point-based framework: BA1 stand-alone benign (-8) + BS1 strong (-4) = -12 points, which maps to Benign.
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
143 / 1,588,976 alleles
gnomAD v4.1: 143 / 1,588,976 alleles. Recorded AF 8.99951e-05. Recorded homozygote count 2.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000417941; MAF= 0.04179%, 117/279944 alleles, homozygotes = 2) and has highest observed frequency in the East Asian population (AF= 0.00564276; MAF= 0.56428%, 110/19494 alleles, homozygotes = 2); grpmax FAF= 0.00484339.
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 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
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: 3 met · 4 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.2198A>G (p.Lys733Arg) variant has been reported in ClinVar as Benign, including an expert-panel benign classification from the ClinGen Brain Malformations Variant Curation Expert Panel.
This variant is present in population databases at a frequency above the Brain Malformations VCEP benign thresholds, with East Asian AF 0.56428% in gnomAD v2.1 and 0.25756% in gnomAD v4.1, exceeding both the BS1 threshold of 0.0185% and the BA1 threshold of 0.0926%.
In silico review does not support a splice-disrupting effect, with SpliceAI max delta score 0.12; REVEL was 0.269 and BayesDel was -0.264459, although PP3 and BP4 are not applicable to this missense gain-of-function interpretation under the Brain Malformations VCEP.
No criteria match.
Met · 3
BA1 Stand aloneThis variant exceeds the Brain Malformations VCEP BA1 threshold of 0.0926%. The highest observed population frequency is East Asian AF 0.56428% in gnomAD v2.1 and 0.25756% in gnomAD v4.1, both above the BA1 threshold. Details ▾Hide ▴
Rule
BA1 if allele frequency > 0.0926% under the Brain Malformations VCEP.
Evidence considered
- gnomAD East Asian frequency
- VCEP BA1 threshold
Sources
BS1 StrongThis variant exceeds the Brain Malformations VCEP BS1 threshold of 0.0185%. The highest observed population frequency is East Asian AF 0.56428% in gnomAD v2.1 and 0.25756% in gnomAD v4.1, both above the BS1 threshold. Details ▾Hide ▴
Rule
BS1 if allele frequency > 0.0185% under the Brain Malformations VCEP.
Evidence considered
- gnomAD East Asian frequency
- VCEP BS1 threshold
Sources
Not met · 4 · evaluated, threshold not reached
PS4 This variant does not meet PM2 because it is present in gnomAD above the VCEP rarity threshold, including East Asian AF 0.56428% in gnomAD v2.1 and 0.25756% in gnomAD v4.1; under the Brain Malformations VCEP, PS4 phenotype points can only be used if PM2 is met. Details ▾Hide ▴
Rule
PS4 requires PM2 first; point-based case enrichment is not applicable when the variant is too frequent in controls.
Evidence considered
- VCEP PS4 prerequisite reviewed
- population frequency review
- ClinVar review
Sources
PM1 The Brain Malformations VCEP allows PM1 at Supporting strength for PIK3CA variants in approved Table 4 domains at amino acids 322-483 or 797-1068. Lys733 falls outside these approved intervals, so PM1 is not met. Details ▾Hide ▴
Rule
PIK3CA PM1_Supporting only for approved Table 4 domains.
Evidence considered
- protein position p.Lys733Arg
- VCEP Table 4 domain ranges
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
PM2 This variant is not absent or rare enough for PM2 because it is present in gnomAD, with East Asian AF 0.56428% in v2.1 and 0.25756% in v4.1, which are well above the VCEP one-person rarity allowance for PM2_Supporting. Details ▾Hide ▴
Rule
PM2_Supporting requires absence/rarity from controls with one person maximum under this VCEP.
Evidence considered
- gnomAD v2.1 frequency
- gnomAD v4.1 frequency
- VCEP PM2 rule
Sources
BS2 BS2 was not met because the Brain Malformations VCEP requires at least 3 homozygotes in gnomAD or at least 3 well-phenotyped family members. This variant has 2 homozygotes in gnomAD v2.1 and 2 homozygotes in gnomAD v4.1, which does not reach the threshold. Details ▾Hide ▴
Rule
BS2 requires ≥3 homozygotes in gnomAD/ExAC or ≥3 well-phenotyped family members.
Evidence considered
- gnomAD homozygote counts
- VCEP BS2 threshold
Sources
Not assessed · 8 · no assessment recorded
PS1 No evidence was identified showing that this exact amino acid change has been established as pathogenic through a different nucleotide change at the same codon. Details ▾Hide ▴
Rule
Brain Malformations VCEP PS1 as originally described.
Evidence considered
- VCEP PS1 rule reviewed
- available case evidence packet reviewed
Still missing
- Need codon-level review for previously established pathogenic alternate nucleotide changes producing p.Lys733Arg.
Sources
PS2 No confirmed de novo or tissue-mosaic evidence was identified for this variant, so the Brain Malformations VCEP requirements for PS2 were not met from the available data. Details ▾Hide ▴
Rule
PS2_Strong requires both absence from confirmed parents and higher allele fraction in affected tissue; PS2_Moderate requires one of those elements under the VCEP specification.
Evidence considered
- VCEP PS2 rule reviewed
- exploratory follow-up summary reviewed
Still missing
- Need parental testing and/or tissue-specific allele fraction data for the exact variant.
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
PS3 No validated functional study for p.Lys733Arg demonstrating an abnormal gain-of-function effect at a level specified by the Brain Malformations VCEP was identified. Details ▾Hide ▴
Rule
Apply only when functional evidence satisfies the SVI and Brain Malformations VCEP assay requirements.
Evidence considered
- VCEP PS3 rule reviewed
- OncoKB variant page reviewed
Still missing
- Need exact-variant functional assay data reviewed against the VCEP/SVI assay-quality framework.
Sources
PM5 No reviewed evidence was identified showing a different missense change at Lys733 that is already established as pathogenic for this disease context. Details ▾Hide ▴
Rule
Brain Malformations VCEP PM5 as originally described.
Evidence considered
- VCEP PM5 rule reviewed
- available case evidence reviewed
Still missing
- Need codon-level review for other pathogenic missense variants at residue 733.
Sources
PP2 The Brain Malformations VCEP allows PP2 for PIK3CA missense variants when the missense constraint z-score is greater than 3.09, but no z-score evidence was provided in the reviewed materials. Details ▾Hide ▴
Rule
PP2_Supporting if missense constraint z-score > 3.09 for PIK3CA.
Evidence considered
- VCEP PP2 rule reviewed
Still missing
- Need the PIK3CA missense constraint z-score source used by the VCEP rule.
Sources
BS3 No validated functional study was identified showing that p.Lys733Arg has a normal or benign effect under the Brain Malformations VCEP/SVI functional evidence framework. Details ▾Hide ▴
Rule
Apply only when functional evidence satisfies the SVI and Brain Malformations VCEP assay requirements for benign effect.
Evidence considered
- VCEP BS3 rule reviewed
- OncoKB variant page reviewed
Still missing
- Need exact-variant benign functional assay data meeting VCEP/SVI quality requirements.
Sources
BP2 No evidence was identified showing that this variant has been observed in cis or trans with a known pathogenic PIK3CA variant. Details ▾Hide ▴
Rule
BP2 if observed in cis or trans with a known pathogenic variant in the same gene.
Evidence considered
- VCEP BP2 rule reviewed
Still missing
- Need phase information with another established pathogenic PIK3CA variant.
Sources
BP5 No evidence was identified showing an alternate molecular explanation for the reported phenotype in a person carrying this variant. Details ▾Hide ▴
Rule
BP5 as originally described.
Evidence considered
- VCEP BP5 rule reviewed
Still missing
- Need case-level alternate diagnosis data if BP5 is to be considered.
Sources
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable under the Brain Malformations VCEP because PIK3CA-related disease is interpreted through a gain-of-function mechanism, and this variant is a missense substitution rather than a null variant. The generic PVS1 scaffold also does not place this variant in a nonsense, frameshift, or canonical splice category. Details ▾Hide ▴
Rule
PVS1 not applicable for this VCEP and not triggered by variant type.
Evidence considered
- VCEP PVS1 applicability statement
- generic PVS1 scaffold review
Sources
PM3 N/AThe Brain Malformations VCEP states that PM3 is not applicable in this framework. Details ▾Hide ▴
Rule
PM3 not applicable for this VCEP.
Evidence considered
- VCEP PM3 applicability statement
Sources
PM4 N/AThe Brain Malformations VCEP states that PM4 is not applicable in this framework. Details ▾Hide ▴
Rule
PM4 not applicable for this VCEP.
Evidence considered
- VCEP PM4 applicability statement
Sources
PM6 N/AThe Brain Malformations VCEP states that PM6 is not applicable in this framework. Details ▾Hide ▴
Rule
PM6 not applicable for this VCEP.
Evidence considered
- VCEP PM6 applicability statement
Sources
PP1 N/AThe Brain Malformations VCEP states that PP1 is not applicable in this disease setting. Details ▾Hide ▴
Rule
PP1 not applicable for this VCEP.
Evidence considered
- VCEP PP1 applicability statement
Sources
PP3 N/AThe Brain Malformations VCEP states that PP3 is not applicable for these gain-of-function PIK3CA variants. Computational results were reviewed but not used for PP3; REVEL was 0.269, BayesDel was -0.264459, and SpliceAI max delta score was 0.12. Details ▾Hide ▴
Rule
PP3 not applicable for Brain Malformations VCEP gain-of-function missense interpretation.
Evidence considered
- VCEP PP3 applicability statement
- REVEL score
- BayesDel score
- SpliceAI score
Sources
PP4 N/AThe Brain Malformations VCEP states that PP4 is not applicable because phenotype specificity is incorporated into PS4. Details ▾Hide ▴
Rule
PP4 not applicable for this VCEP.
Evidence considered
- VCEP PP4 applicability statement
Sources
PP5 N/APP5 is not for use under the ClinGen Sequence Variant Interpretation framework adopted by this VCEP. Details ▾Hide ▴
Rule
PP5 not applicable for this VCEP.
Evidence considered
- VCEP PP5 applicability statement
Sources
BS4 N/AThe Brain Malformations VCEP states that BS4 is not applicable in this disease setting. Details ▾Hide ▴
Rule
BS4 not applicable for this VCEP.
Evidence considered
- VCEP BS4 applicability statement
Sources
BP1 N/ABP1 is not applicable because the Brain Malformations VCEP interprets PIK3CA-related disease through a gain-of-function mechanism rather than a mechanism in which missense change is generally less informative than truncating change. Details ▾Hide ▴
Rule
BP1 not applicable for this VCEP.
Evidence considered
- VCEP disease mechanism guidance
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
BP3 N/AThe Brain Malformations VCEP states that BP3 is not applicable in this framework. Details ▾Hide ▴
Rule
BP3 not applicable for this VCEP.
Evidence considered
- VCEP BP3 applicability statement
Sources
BP4 N/ABP4 is limited by this VCEP to synonymous, intronic non-canonical splice, and UTR variants with no predicted splice effect. This is a missense variant, so BP4 is not applicable, although SpliceAI predicted no significant splice impact with a max delta score of 0.12. Details ▾Hide ▴
Rule
BP4 under this VCEP applies only to synonymous/intronic/UTR variants with no splicing effect.
Evidence considered
- VCEP BP4 applicability statement
- SpliceAI score
Sources
BP7 N/ABP7 is intended for synonymous, intronic non-canonical splice, or UTR variants with low conservation. This is a missense variant, so BP7 is not applicable. Details ▾Hide ▴
Rule
BP7 under this VCEP applies only to synonymous/intronic/UTR variants.
Evidence considered
- VCEP BP7 applicability conditions
Sources
Identifiers
- Gene
- PIK3CA
- Transcript
- NM_006218.2
- Coding (HGVS c.)
- NM_006218.2:c.2198A>G
- Protein (HGVS p.)
- NP_006209.2:p.(Lys733Arg)
- GRCh38
- chr3:179224091 A>G
- GRCh37
- chr3:178941879 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
143 / 1,588,976 alleles
AF 9e-05 · 2 homozygotes · FAF 0.00219
gnomAD v2.1
117 / 279,944 alleles
AF 0.000418 · 2 homozygotes · FAF 0.00484
By genetic ancestry
gnomAD v4.1
AF 9e-05 · 143 / 1,588,976 alleles · 2 hom · FAF 0.0022
| East Asian115 / 44,650 | 0.00262 hom |
| Remaining individuals19 / 61,544 | 0.00031 |
| South Asian5 / 90,218 | 5.5e-05 |
| Admixed American2 / 59,822 | 3.3e-05 |
| African/African American1 / 74,432 | 1.3e-05 |
| European (non-Finnish)1 / 1,158,294 | 8.6e-07 |
0 alternate alleles recorded in 4 other groups: European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish.
gnomAD v2.1
AF 0.00042 · 117 / 279,944 alleles · 2 hom · FAF 0.0048
| East Asian110 / 19,494 | 0.00562 hom |
| Remaining individuals1 / 7,112 | 0.00014 |
| South Asian4 / 30,560 | 0.00013 |
| Admixed American2 / 35,228 | 5.7e-05 |
0 alternate alleles recorded in 4 other groups: African/African American, Ashkenazi Jewish, European (Finnish), European (non-Finnish).
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 8.99951e-05; MAF= 0.00900%, 143/1588976 alleles, homozygotes = 2) and has highest observed frequency in the East Asian population (AF= 0.00257559; MAF= 0.25756%, 115/44650 alleles, homozygotes = 2); grpmax FAF= 0.00219327.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000417941; MAF= 0.04179%, 117/279944 alleles, homozygotes = 2) and has highest observed frequency in the East Asian population (AF= 0.00564276; MAF= 0.56428%, 110/19494 alleles, homozygotes = 2); grpmax FAF= 0.00484339.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 N/AThe Brain Malformations VCEP states that PP3 is not applicable for these gain-of-function PIK3CA variants. Computational results were reviewed but not used for PP3; REVEL was 0.269, BayesDel was -0.264459, and SpliceAI max delta score was 0.12. Details ▾Hide ▴
Rule
PP3 not applicable for Brain Malformations VCEP gain-of-function missense interpretation.
Evidence considered
- VCEP PP3 applicability statement
- REVEL score
- BayesDel score
- SpliceAI score
Sources
BP4 N/ABP4 is limited by this VCEP to synonymous, intronic non-canonical splice, and UTR variants with no predicted splice effect. This is a missense variant, so BP4 is not applicable, although SpliceAI predicted no significant splice impact with a max delta score of 0.12. Details ▾Hide ▴
Rule
BP4 under this VCEP applies only to synonymous/intronic/UTR variants with no splicing effect.
Evidence considered
- VCEP BP4 applicability statement
- SpliceAI score
Sources
BP7 N/ABP7 is intended for synonymous, intronic non-canonical splice, or UTR variants with low conservation. This is a missense variant, so BP7 is not applicable. Details ▾Hide ▴
Rule
BP7 under this VCEP applies only to synonymous/intronic/UTR variants.
Evidence considered
- VCEP BP7 applicability conditions
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.12). REVEL score = 0.269. BayesDel score = -0.264459.
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
143 / 1,588,976 recorded alleles
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/456537/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-178941879-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-179224091-A-G?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006218.2%3Ac.2198…
- OncoKB ↗www.oncokb.org/gene/PIK3CA/K733R
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=108156347
- 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
This variant is present in gnomAD v4.1 (AF= 8.99951e-05; MAF= 0.00900%, 143/1588976 alleles, homozygotes = 2) and has highest observed frequency in the East Asian population (AF= 0.00257559; MAF= 0.25756%, 115/44650 alleles, homozygotes = 2); grpmax FAF= 0.00219327.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000417941; MAF= 0.04179%, 117/279944 alleles, homozygotes = 2) and has highest observed frequency in the East Asian population (AF= 0.00564276; MAF= 0.56428%, 110/19494 alleles, homozygotes = 2); grpmax FAF= 0.00484339.
ClinVar
This variant has been reported in ClinVar as Benign (1 clinical laboratory) and as Benign by ClinGen Brain Malformations Variant Curation Expert Panel (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.12). REVEL score = 0.269. BayesDel score = -0.264459.
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 previously been reported in somatic cancers (COSMIC; COSV55938496, n = 5 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.