About PIK3CA
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PIK3CA c.3140A>G, p.(His1047Arg)
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
PS3Strong
PS3 · strong
Multiple published functional studies showed that p.His1047Arg increases PI3K pathway activity and produces abnormal gain-of-function behavior relative to wild type. Cell-based assays showed higher PI3K activity, growth factor-independent proliferation, anchorage-independent growth, and resistance to anoikis, and in vivo models showed Akt-pathway activation and tumor formation, supporting an abnormal activating effect.
PM1Supporting
PM1 · supporting
This missense variant affects residue 1047, which lies within the PIK3CA kinase-domain interval 797-1068 listed by the Brain Malformations VCEP as an approved PM1 domain. Under this framework, domain membership is sufficient for PM1_Supporting and does not require separate hotspot recurrence evidence.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v4.1 and is present once in gnomAD v2.1 at 1/248274 alleles (AF 0.00040%), with no homozygotes. This meets the VCEP PM2 requirement for absent or very rare population occurrence, which is limited to Supporting strength for this gene group.
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: PS3 strong (+4) + PM1 supporting (+1) + PM2 supporting (+1) + PP5 supporting (+1) = 7 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
This variant is present in gnomAD v2.1 (AF= 4.02781e-06; MAF= 0.00040%, 1/248274 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.9098e-06; MAF= 0.00089%, 1/112236 alleles, homozygotes = 0).
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: Gain-of-function; curated oncogenicity label: Oncogenic.
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.3140A>G (p.His1047Arg) variant has been observed in somatic cancers and is reported in ClinVar, including a Pathogenic expert-panel classification by the ClinGen Brain Malformations Variant Curation Expert Panel.
This variant is absent from gnomAD v4.1 and is present once in gnomAD v2.1 (1/248274 alleles; AF 0.00040%), which is below the VCEP PM2 range and well below the BS1 (>0.0185%) and BA1 (>0.0926%) population thresholds.
Published functional studies showed increased PI3K activity, growth factor-independent and anchorage-independent proliferation, Akt-pathway activation, and tumor formation relative to wild type, consistent with a gain-of-function effect.
SpliceAI predicts no significant splice impact (max delta score 0.04), and REVEL and BayesDel scores are 0.455 and 0.247638, respectively; however, this VCEP does not use PP3 or BP4 for PIK3CA gain-of-function missense variants.
No criteria match.
Met · 4
PS3 StrongMultiple published functional studies showed that p.His1047Arg increases PI3K pathway activity and produces abnormal gain-of-function behavior relative to wild type. Cell-based assays showed higher PI3K activity, growth factor-independent proliferation, anchorage-independent growth, and resistance to anoikis, and in vivo models showed Akt-pathway activation and tumor formation, supporting an abnormal activating effect. Details ▾Hide ▴
Rule
PIK3CA Brain Malformations VCEP: apply PS3 using well-established functional evidence under SVI-aligned specifications.
Evidence considered
- MCF-10A experiments showed higher PI3K activity and transformed phenotypes for H1047R compared with wild type
- In vivo studies showed Akt-pathway activation and tumor formation for H1047R
- Structural study reported a conformational change for His1047Arg that increases membrane association and activity
Still missing
- Direct confirmation against the full VCEP/SVI assay-validation checklist would further reduce uncertainty about final strength assignment.
Sources
PM1 SupportingThis missense variant affects residue 1047, which lies within the PIK3CA kinase-domain interval 797-1068 listed by the Brain Malformations VCEP as an approved PM1 domain. Under this framework, domain membership is sufficient for PM1_Supporting and does not require separate hotspot recurrence evidence. Details ▾Hide ▴
Rule
PIK3CA Brain Malformations VCEP Table 4: PM1_Supporting for variants in approved functional domains.
Evidence considered
- p.His1047Arg falls within the approved kinase-domain interval 797-1068 for PIK3CA
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
PM2 SupportingThis variant is absent from gnomAD v4.1 and is present once in gnomAD v2.1 at 1/248274 alleles (AF 0.00040%), with no homozygotes. This meets the VCEP PM2 requirement for absent or very rare population occurrence, which is limited to Supporting strength for this gene group. Details ▾Hide ▴
Rule
PIK3CA Brain Malformations VCEP: PM2 is Supporting for absent/rare population frequency.
Evidence considered
- gnomAD v4.1 absent
- gnomAD v2.1 total AC 1 of 248274 alleles
- AF 4.027807986337675e-06
- 0 homozygotes
Sources
Not met · 4 · evaluated, threshold not reached
BA1 Population frequency does not meet the BA1 threshold. The variant is absent from gnomAD v4.1 and is present once in gnomAD v2.1 at 0.00040%, which is far below the VCEP BA1 threshold of greater than 0.0926%. Details ▾Hide ▴
Rule
PIK3CA Brain Malformations VCEP: BA1 if AF > 0.0926%.
Evidence considered
- gnomAD v2.1 AF 0.00040%
- gnomAD v4.1 absent
- VCEP BA1 threshold >0.0926%
Sources
BS1 Population frequency does not meet the BS1 threshold. The variant is absent from gnomAD v4.1 and is present once in gnomAD v2.1 at 0.00040%, which is far below the VCEP BS1 threshold of greater than 0.0185%. Details ▾Hide ▴
Rule
PIK3CA Brain Malformations VCEP: BS1 if AF > 0.0185%.
Evidence considered
- gnomAD v2.1 AF 0.00040%
- gnomAD v4.1 absent
- VCEP BS1 threshold >0.0185%
Sources
BS2 BS2 is not met because no homozygotes were observed in gnomAD, and no evidence was identified for at least 3 heterozygous occurrences in well-phenotyped unaffected family members. The available population data show 0 homozygotes. Details ▾Hide ▴
Rule
PIK3CA Brain Malformations VCEP: BS2 requires >=3 homozygotes in gnomAD or >=3 heterozygotes in well-phenotyped family members.
Evidence considered
- gnomAD v2.1 homozygotes 0
- gnomAD v4.1 absent
- No unaffected-family data available
Still missing
- Need evidence of unaffected family members or multiple homozygous population observations if BS2 is to be considered.
Sources
BS3 Available functional evidence does not support a normal or benign effect. Instead, published studies showed increased PI3K signaling, transformation-associated phenotypes, and oncogenic activity, which argues against BS3. Details ▾Hide ▴
Rule
BS3 requires well-established functional evidence showing no damaging effect.
Evidence considered
- Functional studies showed gain-of-function activity rather than normal function
Still missing
- A benign functional interpretation would require well-established studies showing no damaging effect
- which were not identified.
Sources
Not assessed · 7 · no assessment recorded
PS1 No independently verified evidence was identified in the available sources showing a different nucleotide change that produces the same p.His1047Arg amino acid substitution and is already established as pathogenic under this framework. Details ▾Hide ▴
Rule
PS1 requires the same amino acid change as a previously established pathogenic variant.
Evidence considered
- ClinVar entry for this variant was reviewed
- No alternate-nucleotide same-amino-acid evidence was extracted from the available materials
Still missing
- Confirm whether another nucleotide substitution causing p.His1047Arg is documented and classified as pathogenic in a source usable for PS1.
Sources
PS2 No case-level evidence was identified showing confirmed maternity and paternity with absence of the variant in both parents, or tissue-comparison data demonstrating a higher allele fraction in affected tissue than in another tissue, so PS2 cannot be applied from the available evidence. Details ▾Hide ▴
Rule
PIK3CA Brain Malformations VCEP: PS2_Strong requires criteria 1 and 2; PS2_Moderate requires criterion 1 or criterion 2 without parents.
Evidence considered
- VCEP PS2 rule requires parental confirmation and/or tissue mosaicism evidence
- Available materials did not provide case-level parental or tissue-comparison data for this variant
Still missing
- Need exact proband-level parental testing data
- Need affected-tissue versus unaffected-tissue allele-fraction data for this exact variant
Sources
PS4 This variant has been reported in affected individuals and in somatic cancers, but the available materials do not provide a verified Brain Malformations VCEP Table 2A phenotype-point tally for independent cases of this exact variant. Because PS4 in this framework is point based and requires PM2 first plus case-level point assignment, PS4 cannot be fully adjudicated from the available evidence alone. Details ▾Hide ▴
Rule
PIK3CA Brain Malformations VCEP: PS4 strength is determined by Table 2A/2B point totals and requires PM2.
Evidence considered
- ClinVar includes an expert-panel pathogenic classification
- Available materials did not include a complete VCEP phenotype-point calculation for PS4
Still missing
- Need exact independent case count and phenotype categories under Table 2A
- Need verified total PS4 points for this variant in the relevant disease context
Sources
PM5 No independently verified evidence was identified in the available sources showing a different pathogenic missense change at the same residue that can be counted under PM5 for this framework. Details ▾Hide ▴
Rule
PM5 requires a novel missense change at an amino acid residue where a different missense change is established as pathogenic.
Evidence considered
- Available materials were reviewed for codon-level evidence
- No codon-1047 alternate pathogenic substitution was independently adjudicated from the provided sources
Still missing
- Confirm whether other pathogenic missense substitutions at codon 1047 are documented in usable primary or curated sources for PM5.
Sources
PP2 The VCEP allows PP2 for PIK3CA if the missense constraint z-score is greater than 3.09, but no verified z-score value was provided in the available evidence files, so PP2 cannot be applied from the current record. Details ▾Hide ▴
Rule
PIK3CA Brain Malformations VCEP: award PP2 if missense constraint z-score > 3.09.
Evidence considered
- VCEP PP2 rule requires missense z-score > 3.09
- No z-score value was available in the reviewed case evidence
Still missing
- Need the gene-level missense constraint z-score used by this framework.
Sources
BP2 No evidence was identified showing this variant in cis or in trans with another established pathogenic PIK3CA variant, so BP2 cannot be assessed from the available data. Details ▾Hide ▴
Rule
BP2 may be applied when the variant is observed in cis or trans with a known pathogenic variant.
Evidence considered
- No cis/trans phase data were available
Still missing
- Need phased genotype evidence with a known pathogenic PIK3CA variant.
Sources
BP5 No alternate molecular diagnosis or other established explanation for the phenotype was identified in the available evidence, so BP5 cannot be applied. Details ▾Hide ▴
Rule
BP5 may be applied when another molecular basis for disease is established.
Evidence considered
- No alternate molecular diagnosis was documented
Still missing
- Need verified evidence of an alternative molecular basis for the phenotype.
Sources
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable for this missense variant because the Brain Malformations VCEP specifies that PIK3CA-related disease is driven by gain of function rather than loss of function, and this variant is not a null-variant type in the generic PVS1 framework. Details ▾Hide ▴
Rule
PIK3CA Brain Malformations VCEP: PVS1 not applicable for gain-of-function disease.
Evidence considered
- VCEP guidance states PVS1 is not applicable for PIK3CA gain-of-function disease
- Variant is a missense substitution p.His1047Arg rather than a nonsense
- frameshift
- or canonical splice variant
Sources
PM3 N/APM3 is not applicable in this VCEP framework for PIK3CA-related gain-of-function disease. Details ▾Hide ▴
Rule
PIK3CA Brain Malformations VCEP: PM3 not applicable.
Evidence considered
- VCEP marks PM3 as not applicable
Sources
PM4 N/APM4 is not applicable in this VCEP framework, and this variant is a missense substitution rather than a protein length-changing variant. Details ▾Hide ▴
Rule
PIK3CA Brain Malformations VCEP: PM4 not applicable.
Evidence considered
- VCEP marks PM4 as not applicable
- Variant is missense
Sources
PM6 N/APM6 is not applicable in this VCEP framework for PIK3CA-related disease. Details ▾Hide ▴
Rule
PIK3CA Brain Malformations VCEP: PM6 not applicable.
Evidence considered
- VCEP marks PM6 as not applicable
Sources
PP1 N/APP1 is not applicable in this VCEP framework because these disorders are typically de novo, germline mosaic, or post-zygotic rather than segregation-based Mendelian presentations suitable for PP1 scoring. Details ▾Hide ▴
Rule
PIK3CA Brain Malformations VCEP: PP1 not applicable.
Evidence considered
- VCEP marks PP1 as not applicable
Sources
PP3 N/APP3 is not applicable for this PIK3CA gain-of-function missense variant under the Brain Malformations VCEP. Computational results were reviewed: SpliceAI max delta score was 0.04, REVEL was 0.455, and BayesDel was 0.247638, but this framework does not use PP3 for PIK3CA gain-of-function missense interpretation. Details ▾Hide ▴
Rule
PIK3CA Brain Malformations VCEP: PP3 not applicable for gain-of-function variants.
Evidence considered
- SpliceAI max delta 0.04
- REVEL 0.455
- BayesDel 0.247638
Sources
PP4 N/APP4 is not applicable in this VCEP because phenotype specificity is incorporated into PS4 rather than scored separately. Details ▾Hide ▴
Rule
PIK3CA Brain Malformations VCEP: PP4 not applicable.
Evidence considered
- VCEP marks PP4 as not applicable because phenotype evidence is accounted for under PS4
Sources
BS4 N/ABS4 is not applicable in this VCEP framework. Details ▾Hide ▴
Rule
PIK3CA Brain Malformations VCEP: BS4 not applicable.
Evidence considered
- VCEP marks BS4 as not applicable
Sources
BP1 N/ABP1 is not applicable for PIK3CA in this VCEP because the disease mechanism is gain of function rather than a context in which truncating variants would predominate over missense variants. Details ▾Hide ▴
Rule
PIK3CA Brain Malformations VCEP: BP1 not applicable.
Evidence considered
- VCEP guidance states BP1 is not applicable
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
BP3 N/ABP3 is not applicable in this VCEP framework. Details ▾Hide ▴
Rule
PIK3CA Brain Malformations VCEP: BP3 not applicable.
Evidence considered
- VCEP marks BP3 as not applicable
Sources
BP4 N/ABP4 is not applicable for this missense variant under the Brain Malformations VCEP because BP4 is restricted to synonymous, intronic, or UTR variants with no predicted splice effect. SpliceAI showed a max delta score of 0.04, but this does not make BP4 applicable to a missense variant in this framework. Details ▾Hide ▴
Rule
PIK3CA Brain Malformations VCEP: BP4 is limited to synonymous/intronic/UTR variants with no splicing impact.
Evidence considered
- Variant is missense
- SpliceAI max delta 0.04
Sources
BP6 N/ABP6 is not applicable in this VCEP framework. Details ▾Hide ▴
Rule
PIK3CA Brain Malformations VCEP: BP6 not applicable.
Evidence considered
- VCEP marks BP6 as not applicable
Sources
BP7 N/ABP7 is not applicable because this is a missense variant rather than a synonymous, intronic, or UTR change. Details ▾Hide ▴
Rule
PIK3CA Brain Malformations VCEP: BP7 applies to synonymous/intronic/UTR variants only.
Evidence considered
- Variant is missense
Sources
Identifiers
- Gene
- PIK3CA
- Transcript
- NM_006218.2
- Coding (HGVS c.)
- NM_006218.2:c.3140A>G
- Protein (HGVS p.)
- NP_006209.2:p.(His1047Arg)
- GRCh38
- chr3:179234297 A>G
- GRCh37
- chr3:178952085 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
1 / 248,274 alleles
AF 4.03e-06 · 0 homozygotes
By genetic ancestry
gnomAD v2.1
AF 4e-06 · 1 / 248,274 alleles · 0 hom
| European (non-Finnish)1 / 112,236 | 8.9e-06 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.02781e-06; MAF= 0.00040%, 1/248274 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.9098e-06; MAF= 0.00089%, 1/112236 alleles, homozygotes = 0).
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 N/APP3 is not applicable for this PIK3CA gain-of-function missense variant under the Brain Malformations VCEP. Computational results were reviewed: SpliceAI max delta score was 0.04, REVEL was 0.455, and BayesDel was 0.247638, but this framework does not use PP3 for PIK3CA gain-of-function missense interpretation. Details ▾Hide ▴
Rule
PIK3CA Brain Malformations VCEP: PP3 not applicable for gain-of-function variants.
Evidence considered
- SpliceAI max delta 0.04
- REVEL 0.455
- BayesDel 0.247638
Sources
BP4 N/ABP4 is not applicable for this missense variant under the Brain Malformations VCEP because BP4 is restricted to synonymous, intronic, or UTR variants with no predicted splice effect. SpliceAI showed a max delta score of 0.04, but this does not make BP4 applicable to a missense variant in this framework. Details ▾Hide ▴
Rule
PIK3CA Brain Malformations VCEP: BP4 is limited to synonymous/intronic/UTR variants with no splicing impact.
Evidence considered
- Variant is missense
- SpliceAI max delta 0.04
Sources
BP7 N/ABP7 is not applicable because this is a missense variant rather than a synonymous, intronic, or UTR change. Details ▾Hide ▴
Rule
PIK3CA Brain Malformations VCEP: BP7 applies to synonymous/intronic/UTR variants only.
Evidence considered
- Variant is missense
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.455. BayesDel score = 0.247638.
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/13652/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-178952085-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-179234297-A-G?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006218.2%3Ac.3140…
- OncoKB ↗www.oncokb.org/gene/PIK3CA/H1047R
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=108143886
- 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
This variant is present in gnomAD v2.1 (AF= 4.02781e-06; MAF= 0.00040%, 1/248274 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.9098e-06; MAF= 0.00089%, 1/112236 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Pathogenic (25 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 = 0.04). REVEL score = 0.455. BayesDel score = 0.247638.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Oncogenic.
Somatic
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55873195, n = 3817 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.