About PIK3CA
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PIK3CA c.2015+9A>G, p.?
Classification
Likely benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.
Likely benign.A likely 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: 2
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 2
BS1Strong
BS1 · strong
The BS1 threshold in this VCEP is >0.0185%. This variant exceeds that threshold in gnomAD, with African/African American AF 0.08591% in v2.1 and 0.09391% in v4.1, supporting BS1.
BP6Supporting
BP6 · supporting
Expert panel ClinGen Brain Malformations Variant Curation Expert Panel classified as Likely benign.
Recorded classification: Likely benign
Brain Malformations Specification Tavtigian point framework v1.1.0 point-based framework: BS1 strong (-4) = -4 points, which maps to Likely 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
90 / 1,549,338 alleles
gnomAD v4.1: 90 / 1,549,338 alleles. Recorded AF 5.80893e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00012416; MAF= 0.01242%, 31/249678 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000859107; MAF= 0.08591%, 20/23280 alleles, homozygotes = 0); grpmax FAF= 0.00052743.
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.
No screenshot for this evidence
Functional evidence
Not recorded
No standalone functional evidence summary is recorded in evidence_summary.functional.
No listed criterion applied
OncoKB ↗
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Context only
COSMIC ↗
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 · 5 not met · 7 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 NM_006218.2:c.2015+9A>G (NP_006209.2:p.?) variant has been reported in ClinVar, where the aggregate classification is likely benign and the ClinGen Brain Malformations Variant Curation Expert Panel has classified it as likely benign.
This variant is present in population databases at a frequency above the Brain Malformations VCEP BS1 threshold of 0.0185%, including 31/249678 alleles in gnomAD v2.1 (AF 0.01242%) and a highest observed African/African American frequency of 0.09391% in gnomAD v4.1.
No variant-specific functional study was identified showing either an abnormal or a normal effect on PIK3CA splicing or function.
Available computational splicing evidence could not be independently confirmed as a complete 2-of-3 benign prediction set, so BP4 and BP7 were not applied from the available records.
No criteria match.
Met · 2
BS1 StrongThe BS1 threshold in this VCEP is >0.0185%. This variant exceeds that threshold in gnomAD, with African/African American AF 0.08591% in v2.1 and 0.09391% in v4.1, supporting BS1. Details ▾Hide ▴
Rule
BS1_Strong if allele frequency is >0.0185% under the VCEP specification.
Evidence considered
- gnomAD v2.1 African/African American AF 0.08591%
- gnomAD v4.1 African/African American AF 0.09391%
Sources
BP6 SupportingExpert panel ClinGen Brain Malformations Variant Curation Expert Panel classified as Likely benign. Details ▾Hide ▴
Not met · 5 · evaluated, threshold not reached
PS4 No case-series or enrichment data were identified for this exact variant, and the prerequisite PM2 criterion is not met because this variant is present in gnomAD above a single-observation level. PS4 is therefore not met. Details ▾Hide ▴
Rule
PS4 point-based case enrichment can only be used if PM2 is satisfied.
Evidence considered
- ClinVar record exists but no evidence of multiple affected cases sufficient for PS4
- Population frequency exceeds the VCEP PM2 rarity expectation
Still missing
- Variant-specific affected-case counts with VCEP phenotype-point assignment
Sources
PM1 This variant is intronic at c.2015+9 and does not alter a protein residue within the PIK3CA Table 4 critical functional domains, so PM1 is not met. Details ▾Hide ▴
Rule
PM1_Supporting for residues affecting approved critical functional domains.
Evidence considered
- PIK3CA Table 4 PM1 applies to residues within approved kinase-domain intervals
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
PM2 The Brain Malformations VCEP allows PM2 only for variants absent or extremely rare in controls, with one person maximum. This variant is present in gnomAD v2.1 at 31/249678 alleles (AF 0.01242%) and in gnomAD v4.1 at AF 0.00581%, with the highest observed African/African American frequency 0.09391%, so PM2 is not met. Details ▾Hide ▴
Rule
PM2_Supporting requires absent/rare from controls in an ethnically matched cohort population sample; local guidance indicates one person maximum.
Evidence considered
- gnomAD v2.1 total AC 31
- gnomAD v4.1 population frequency well above a one-observation rarity threshold
Sources
BA1 The BA1 threshold in this VCEP is >0.0926%. Although the highest observed African/African American frequency in gnomAD v4.1 is 0.09391%, the joint grpmax filtering allele frequency is 0.07593%, below the BA1 threshold, so BA1 was not applied from the available population evidence. Details ▾Hide ▴
Rule
BA1 if allele frequency is >0.0926% under the VCEP specification.
Evidence considered
- gnomAD v4.1 best subpopulation AF 0.09391%
- gnomAD v4.1 joint grpmax FAF 0.07593%
Still missing
- Population-threshold interpretation should be confirmed if the VCEP intends raw subpopulation AF rather than conservative filtering AF
Sources
BS2 BS2 requires at least 3 homozygotes in gnomAD or at least 3 well-phenotyped unaffected family members. No homozygotes were observed in gnomAD v2.1 or v4.1, and no unaffected family data were identified, so BS2 is not met. Details ▾Hide ▴
Rule
BS2 requires ≥3 homozygotes in gnomAD or ≥3 well-phenotyped family members.
Evidence considered
- 0 homozygotes in gnomAD v2.1
- 0 homozygotes in gnomAD v4.1
Still missing
- Well-phenotyped unaffected carrier data
Sources
Not assessed · 7 · no assessment recorded
PS2 No confirmed de novo or tissue-mosaic case data with parental testing were identified for this exact variant, so PS2 cannot be assessed from the available evidence. Details ▾Hide ▴
Rule
PS2_Strong requires both parental absence and tissue distribution evidence; PS2_Moderate requires one of these under the VCEP specification.
Evidence considered
- No exact de novo or mosaic case-level evidence for this variant was identified
Still missing
- Parental testing with confirmed maternity and paternity
- Tissue comparison showing higher or exclusive variant allele fraction in affected tissue
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
PS3 No published RNA study, minigene assay, or other well-established functional assay was identified for this exact intronic variant, so PS3 cannot be applied. Details ▾Hide ▴
Rule
Well-established functional studies supportive of a damaging effect under the Brain Malformations VCEP specifications.
Evidence considered
- No variant-specific functional evidence identified
Still missing
- Direct RNA or minigene evidence for splicing effect
- Validated functional assay data specific to c.2015+9A>G
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
BS3 No well-established study was identified showing that this variant has no effect on splicing or downstream PIK3CA function, so BS3 cannot be applied. Details ▾Hide ▴
Rule
Well-established functional studies show no damaging effect on protein function or splicing.
Evidence considered
- No benign functional evidence identified for this exact variant
Still missing
- Variant-specific negative RNA or functional study
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
BP2 No phase data were identified showing this variant in cis or trans with a known pathogenic PIK3CA variant, so BP2 cannot be assessed. Details ▾Hide ▴
Rule
Observed in cis or trans with a known pathogenic variant in the same gene.
Evidence considered
- No cis/trans observation data identified
Still missing
- Phase information with another pathogenic PIK3CA variant
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
BP4 BP4 for this VCEP requires at least 2 of 3 splicing tools to predict no splicing impact for an intronic non-canonical variant. A SpliceAI source was available, but no independently retrievable SpliceAI, varSEAK, and MaxEntScan result set was available to confirm a 2-of-3 benign splicing pattern, so BP4 could not be assessed. Details ▾Hide ▴
Rule
BP4_Supporting for synonymous or intronic non-canonical variants if 2 of 3 splicing tools predict no impact.
Evidence considered
- Intronic non-canonical splice-region variant
- No complete 2-of-3 benign splicing prediction set available
Still missing
- SpliceAI result
- varSEAK result
- MaxEntScan result
Sources
BP5 No alternate molecular diagnosis was identified that would explain the phenotype independently of this variant, so BP5 cannot be assessed. Details ▾Hide ▴
Rule
Variant found in a case with an alternate molecular basis for disease.
Evidence considered
- No alternate molecular basis identified
Still missing
- Independent alternate molecular diagnosis
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
BP7 BP7 for this VCEP requires a non-canonical intronic variant at a non-conserved nucleotide with PhyloP <0.1. No PhyloP conservation value was available to confirm this threshold, so BP7 could not be assessed. Details ▾Hide ▴
Rule
BP7_Supporting for synonymous or intronic non-canonical variants if the nucleotide is non-conserved (PhyloP <0.1).
Evidence considered
- Variant is intronic and outside the canonical splice dinucleotide
Still missing
- PhyloP conservation score for the altered nucleotide
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable in the Brain Malformations PIK3CA framework because the disease mechanism is gain of function rather than loss of function, and this variant is also outside the canonical ±1,2 splice positions. Details ▾Hide ▴
Rule
Null-variant criterion; not applicable for this gain-of-function VCEP.
Evidence considered
- VCEP marks PVS1 not applicable for PIK3CA
- Variant is c.2015+9A>G
- not a canonical splice-site change
Sources
PS1 N/AThis is an intronic c.2015+9A>G variant and does not create the same amino acid change as an established pathogenic missense variant, so PS1 is not applicable. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic variant.
Evidence considered
- Intronic splice-region variant without a defined amino acid substitution
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
PM3 N/APM3 is not applicable because this VCEP addresses disorders caused by heterozygous de novo or mosaic PIK3CA variants rather than a recessive biallelic mechanism. Details ▾Hide ▴
Rule
Detected in trans with a pathogenic variant for a recessive disorder.
Evidence considered
- VCEP states PM3 is not applicable
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
PM4 N/APM4 is not applicable under this VCEP framework. Details ▾Hide ▴
Rule
Protein length changes due to in-frame deletions/insertions or stop-loss variants.
Evidence considered
- VCEP states PM4 is not applicable
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
PM5 N/AThis is not a missense change at an amino acid residue, so PM5 is not applicable. Details ▾Hide ▴
Rule
Novel missense change at an amino acid residue where a different pathogenic missense change has been seen before.
Evidence considered
- Intronic splice-region variant without an amino acid substitution
Sources
PM6 N/APM6 is not applicable under this VCEP framework. Details ▾Hide ▴
Rule
Assumed de novo without confirmation of paternity and maternity.
Evidence considered
- VCEP states PM6 is not applicable
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
PP1 N/APP1 is not applicable because the relevant PIK3CA disease mechanism in this framework is typically de novo or mosaic rather than familial segregation. Details ▾Hide ▴
Rule
Co-segregation with disease in multiple affected family members.
Evidence considered
- VCEP states PP1 is not applicable
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
PP2 N/APP2 is a missense-specific rule based on missense constraint, and this variant is intronic, so PP2 is not applicable. Details ▾Hide ▴
Rule
Award PP2 if the missense constraint z-score is >3.09.
Evidence considered
- Variant is not missense
Sources
PP3 N/APP3 is not applicable in this Brain Malformations VCEP because PIK3CA disease is driven by gain-of-function variants and the specification does not use traditional computational pathogenicity prediction for this purpose. Details ▾Hide ▴
Rule
Multiple lines of computational evidence support a deleterious effect.
Evidence considered
- VCEP states PP3 is not applicable for these gain-of-function genes
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
PP4 N/APP4 is not applicable in this framework because phenotype specificity is accounted for under PS4. Details ▾Hide ▴
Rule
Patient phenotype or family history highly specific for a disease with a single genetic etiology.
Evidence considered
- VCEP states PP4 is not applicable
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
PP5 N/APP5 is not used by this VCEP. Details ▾Hide ▴
Rule
Reputable source recently reports variant as pathogenic without available evidence.
Evidence considered
- VCEP states PP5 is not applicable
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
BS4 N/ABS4 is not applicable in this framework. Details ▾Hide ▴
Rule
Lack of segregation in affected family members.
Evidence considered
- VCEP states BS4 is not applicable
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
BP1 N/ABP1 is not applicable because loss of function is not the relevant disease mechanism in this PIK3CA framework. Details ▾Hide ▴
Rule
Missense variant in a gene where primarily truncating variants cause disease.
Evidence considered
- VCEP states BP1 is not applicable
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
BP3 N/ABP3 is not applicable under this VCEP framework. Details ▾Hide ▴
Rule
In-frame deletion/insertion in a repetitive region without known function.
Evidence considered
- VCEP states BP3 is not applicable
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
Identifiers
- Gene
- PIK3CA
- Transcript
- NM_006218.2
- Coding (HGVS c.)
- NM_006218.2:c.2015+9A>G
- Protein (HGVS p.)
- NP_006209.2:p.?
- GRCh38
- chr3:179220061 A>G
- GRCh37
- chr3:178937849 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
—
Transcript span
—
Strand
—
Variants mapped
—
Source
UCSC ncbiRefSeqCurated
All variants in PIK3CA
—
Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
90 / 1,549,338 alleles
AF 5.81e-05 · 0 homozygotes · FAF 0.000759
gnomAD v2.1
31 / 249,678 alleles
AF 0.000124 · 0 homozygotes · FAF 0.000527
By genetic ancestry
gnomAD v4.1
AF 5.8e-05 · 90 / 1,549,338 alleles · 0 hom · FAF 0.00076
| African/African American68 / 72,406 | 0.00094 |
| Admixed American10 / 50,446 | 0.0002 |
| Remaining individuals5 / 59,892 | 8.3e-05 |
| South Asian1 / 82,454 | 1.2e-05 |
| European (non-Finnish)6 / 1,142,370 | 5.3e-06 |
0 alternate alleles recorded in 5 other groups: European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish.
gnomAD v2.1
AF 0.00012 · 31 / 249,678 alleles · 0 hom · FAF 0.00053
| African/African American20 / 23,280 | 0.00086 |
| Admixed American9 / 26,068 | 0.00035 |
| Remaining individuals1 / 6,166 | 0.00016 |
| European (non-Finnish)1 / 119,282 | 8.4e-06 |
0 alternate alleles recorded in 4 other groups: Ashkenazi Jewish, East Asian, European (Finnish), South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 5.80893e-05; MAF= 0.00581%, 90/1549338 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000939149; MAF= 0.09391%, 68/72406 alleles, homozygotes = 0); grpmax FAF= 0.00075934.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00012416; MAF= 0.01242%, 31/249678 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000859107; MAF= 0.08591%, 20/23280 alleles, homozygotes = 0); grpmax FAF= 0.00052743.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 BP4 for this VCEP requires at least 2 of 3 splicing tools to predict no splicing impact for an intronic non-canonical variant. A SpliceAI source was available, but no independently retrievable SpliceAI, varSEAK, and MaxEntScan result set was available to confirm a 2-of-3 benign splicing pattern, so BP4 could not be assessed. Details ▾Hide ▴
Rule
BP4_Supporting for synonymous or intronic non-canonical variants if 2 of 3 splicing tools predict no impact.
Evidence considered
- Intronic non-canonical splice-region variant
- No complete 2-of-3 benign splicing prediction set available
Still missing
- SpliceAI result
- varSEAK result
- MaxEntScan result
Sources
BP7 BP7 for this VCEP requires a non-canonical intronic variant at a non-conserved nucleotide with PhyloP <0.1. No PhyloP conservation value was available to confirm this threshold, so BP7 could not be assessed. Details ▾Hide ▴
Rule
BP7_Supporting for synonymous or intronic non-canonical variants if the nucleotide is non-conserved (PhyloP <0.1).
Evidence considered
- Variant is intronic and outside the canonical splice dinucleotide
Still missing
- PhyloP conservation score for the altered nucleotide
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
PP3 N/APP3 is not applicable in this Brain Malformations VCEP because PIK3CA disease is driven by gain-of-function variants and the specification does not use traditional computational pathogenicity prediction for this purpose. Details ▾Hide ▴
Rule
Multiple lines of computational evidence support a deleterious effect.
Evidence considered
- VCEP states PP3 is not applicable for these gain-of-function genes
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
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
90 / 1,549,338 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 ↗
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/412646/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-178937849-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-179220061-A-G?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006218.2%3Ac.2015…
- OncoKB ↗www.oncokb.org/gene/PIK3CA/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PIK3CA+c.2015+9A%3EG
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= 5.80893e-05; MAF= 0.00581%, 90/1549338 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000939149; MAF= 0.09391%, 68/72406 alleles, homozygotes = 0); grpmax FAF= 0.00075934.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00012416; MAF= 0.01242%, 31/249678 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000859107; MAF= 0.08591%, 20/23280 alleles, homozygotes = 0); grpmax FAF= 0.00052743.
ClinVar
This variant has been reported in ClinVar as Likely benign (1 clinical laboratory) and as Benign (1 clinical laboratory) and as Likely 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 = 0.00).
Somatic
This variant has not previously been reported in somatic cancers (COSMIC).