About PIK3CA
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PIK3CA c.1911+19G>T, p.?
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: 1
Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
NM_006218.4:c.1911+19G>T is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Under the Brain Malformations VCEP, PM2 is awarded at Supporting strength when the variant is absent or rare (≤1) in ethnically-matched population controls.
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; combination = 1 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
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. 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 ↗
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
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Context only
COSMIC ↗
For specialists
Technical detail
ACMG/AMP criteria under ClinGen PIK3CA VCEP v1.1, with the data and sources behind each one.
27 criteria with recorded statuses: 1 met · 9 not met · 2 not assessed · 15 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.1911+19G>T is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at Supporting strength under the Brain Malformations VCEP v1.1.
No affected individuals have been reported with this variant; it is absent from ClinVar, COSMIC, and the literature, yielding zero points for PS4 under Table 2A.
PVS1, PP3, and BP1 are not applicable under the Brain Malformations VCEP because the PIK3CA disease mechanism for cerebral malformations is gain-of-function.
The variant is intronic (c.1911+19) and does not alter an amino acid residue; splice prediction by SpliceAI shows no significant impact (max delta score = 0.01). PS1, PM1, PM5, and PP2 are not applicable because they require amino acid-level changes.
BP4 and BP7 could not be fully assessed — BP4 requires two of three splicing tools (only SpliceAI available; missing varSEAK and MaxEntScan) and BP7 requires a PhyloP conservation score (unavailable).
Applying the Brain Malformations VCEP Tavtigian point framework: only PM2_Supporting (+1 point) is met. Total score of +1 falls in the VUS range (0-5 points).
No criteria match.
Met · 1
PM2 SupportingNM_006218.4:c.1911+19G>T is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Under the Brain Malformations VCEP, PM2 is awarded at Supporting strength when the variant is absent or rare (≤1) in ethnically-matched population controls. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes). Absent from gnomAD v4.1 (exomes). Absent from gnomAD-Canada v1.0 (genomes). VCEP PM2 rule: Supporting strength when absent/rare (≤1).
Sources
Not met · 9 · evaluated, threshold not reached
PS2 No de novo observation has been reported for NM_006218.4:c.1911+19G>T. The variant is absent from ClinVar and no literature reports describe de novo occurrence with confirmed maternity and paternity. Details ▾Hide ▴
Evidence considered
- Variant is absent from ClinVar
- no de novo reports identified in any evidence source.
Still missing
- No parental or tissue-based de novo data available for this variant.
Sources
PS3 No functional studies have been reported for NM_006218.4:c.1911+19G>T. Zero PMIDs were identified across all evidence sources. The variant has not been directly tested and no systematically characterized range includes this intronic position. Details ▾Hide ▴
Evidence considered
- No publications identified
- literature_pass reports 0 total PMIDs.
Still missing
- No functional data available for this variant or for a systematically characterized range spanning c.1911+19.
PS4 PS4 requires phenotype-confirmed cases scored under Table 2A and PM2 must be met first. Although PM2_Supporting is met (variant absent from gnomAD), zero affected individuals have been reported with NM_006218.4:c.1911+19G>T in ClinVar, COSMIC, or the literature, yielding 0 phenotype points. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar (no reported cases). Absent from COSMIC. Absent from all gnomAD datasets. Zero points from Table 2A.
Still missing
- No affected individuals reported with this variant.
Sources
BA1 BA1 requires allele frequency > 0.0926% under the Brain Malformations VCEP. NM_006218.4:c.1911+19G>T is absent from gnomAD v2.1, v4.1, and gnomAD-Canada; the observed frequency is zero and does not meet the BA1 threshold. Details ▾Hide ▴
Evidence considered
- Absent from all gnomAD datasets. VCEP BA1 threshold: allele frequency > 0.0926%. Observed frequency: 0%.
Sources
BS1 BS1 requires allele frequency > 0.0185% under the Brain Malformations VCEP. NM_006218.4:c.1911+19G>T is absent from all population databases; the observed frequency of zero does not meet the BS1 threshold. Details ▾Hide ▴
Evidence considered
- Absent from all gnomAD datasets. VCEP BS1 threshold: allele frequency > 0.0185%. Observed frequency: 0%.
Sources
BS2 BS2 requires ≥3 homozygotes in gnomAD or ≥3 heterozygous in well-phenotyped family members. NM_006218.4:c.1911+19G>T is absent from gnomAD with zero homozygotes, and no family member phenotype data is available. Details ▾Hide ▴
Evidence considered
- Zero homozygotes in gnomAD (variant absent). No well-phenotyped heterozygous family members reported.
Still missing
- No family member phenotype data available.
Sources
BS3 BS3 requires well-established in vitro or in vivo functional studies showing no damaging effect. No functional studies have been reported for NM_006218.4:c.1911+19G>T; zero publications were identified. Details ▾Hide ▴
Evidence considered
- No functional studies identified for this variant. Zero PMIDs across all evidence sources.
Still missing
- No functional data available to assess potential benign impact.
BP2 BP2 requires observation of the variant in cis or trans with a known pathogenic variant in the same gene. No phase data or co-occurrence reports are available for NM_006218.4:c.1911+19G>T. Details ▾Hide ▴
Evidence considered
- No cis/trans phase data available
- variant absent from ClinVar and literature.
Still missing
- No phase or co-occurrence data with known PIK3CA pathogenic variants.
BP5 BP5 requires the variant to be found in a case with an alternate molecular basis for disease. No such case has been reported for NM_006218.4:c.1911+19G>T. Details ▾Hide ▴
Evidence considered
- No reports of this variant co-occurring with an alternate molecular diagnosis.
Still missing
- No data on alternate molecular diagnoses in carriers of this variant.
Not assessed · 2 · no assessment recorded
BP4 BP4 under the Brain Malformations VCEP applies to intronic variants (except canonical splice sites) and requires two of three splicing prediction tools (varSEAK, SpliceAI, MaxEntScan) to predict no impact. SpliceAI predicts no impact (max delta score = 0.01), but varSEAK and MaxEntScan scores are unavailable. Criterion cannot be fully adjudicated with only one of three required tools. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.01 (no splice impact). VarSEAK and MaxEntScan scores not available.
Still missing
- Missing varSEAK and MaxEntScan splicing predictions
- need 2 of 3 tools to apply BP4 per VCEP specification.
Sources
BP7 BP7 under the Brain Malformations VCEP applies to intronic positions (except canonical splice sites) and requires the nucleotide to be non-conserved (PhyloP score < 0.1). PhyloP conservation score is not available for this variant position, preventing adjudication. Details ▾Hide ▴
Evidence considered
- Variant is intronic at c.1911+19
- not a canonical splice site. PhyloP conservation score not available for this genomic position.
Still missing
- PhyloP conservation score required for BP7 adjudication per VCEP specification.
Sources
Not applicable · 15· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 VCEPPVS1 is not applicable for PIK3CA under the Brain Malformations VCEP v1.1 because the disease mechanism is gain-of-function, not loss-of-function or haploinsufficiency. Details ▾Hide ▴
Evidence considered
- VCEP specification explicitly designates PVS1 as Not Applicable: 'LOF and/or haploinsufficiency have not been clearly identified as disease mechanisms underlying brain malformations related to these genes.'
Sources
PS1 N/APS1 requires a same amino acid change as a previously established pathogenic variant. NM_006218.4:c.1911+19G>T is intronic and does not produce an amino acid change; no residue is altered. Details ▾Hide ▴
Evidence considered
- Intronic variant at position c.1911+19 does not alter any amino acid residue.
Sources
PM1 N/APM1 under the Brain Malformations VCEP applies to residues affecting critical functional domains in Table 4 (PIK3CA kinase domains AA 322-483 and AA 797-1068). NM_006218.4:c.1911+19G>T is intronic and does not alter any amino acid residue, so no residue-level domain assessment applies. Details ▾Hide ▴
Evidence considered
- VCEP PM1 rule specifies 'Residues affecting critical functional domains.' This intronic variant does not change a residue.
Sources
PM5 N/APM5 applies to novel missense changes at an amino acid residue where a different missense change has been established as pathogenic. NM_006218.4:c.1911+19G>T is intronic and does not produce an amino acid change; no residue for comparator analysis. Details ▾Hide ▴
Evidence considered
- Intronic variant with no amino acid change. pm5_candidates confirms not eligible for classic same-residue missense PM5.
Sources
cspec ↗pm5_candidates
PM6 VCEPPM6 is designated as Not Applicable by the Brain Malformations VCEP v1.1; assumed de novo without confirmation of maternity/paternity is addressed under PS2 instead. Details ▾Hide ▴
Evidence considered
- VCEP specification: 'This point is addressed according to PS2 and will not be used.'
Sources
PP1 VCEPPP1 is designated as Not Applicable by the Brain Malformations VCEP v1.1; disease-causing variants in PIK3CA-associated brain malformations are germline mosaic, de novo, or mosaic, making co-segregation analysis inappropriate. Details ▾Hide ▴
Evidence considered
- VCEP specification: 'Not applicable since disease-causing variants are germline mosaic
- de novo or mosaic.'
Sources
PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation (z-score > 3.09). NM_006218.4:c.1911+19G>T is an intronic variant, not a missense variant, and does not fall within the intended scope of this criterion. Details ▾Hide ▴
Evidence considered
- Intronic variant at position c.1911+19
- PP2 is designed for missense variants in constrained genes.
Sources
PP3 VCEPPP3 is designated as Not Applicable by the Brain Malformations VCEP v1.1; traditional mutation pathogenicity prediction algorithms focus on loss-of-function mechanisms and are not validated for gain-of-function variants in PIK3CA. Details ▾Hide ▴
Evidence considered
- VCEP specification: 'Not applicable since these variants are GOF
- and traditional mutation pathogenicity prediction algorithms focus on LOF mechanisms.'
Sources
PP4 VCEPPP4 is designated as Not Applicable by the Brain Malformations VCEP v1.1; patient phenotype specificity is accounted for under the PS4 point-based scoring system instead. Details ▾Hide ▴
Evidence considered
- VCEP specification: 'Not applicable since this criterion is accounted for under PS4.'
Sources
PP5 VCEPPP5 is designated as Not Applicable by the Brain Malformations VCEP v1.1 per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. Additionally, this variant is absent from ClinVar and has no prior classification from any source. Details ▾Hide ▴
BS4 VCEPBS4 is designated as Not Applicable by the Brain Malformations VCEP v1.1 because disease-causing variants in PIK3CA-associated brain malformations are de novo, germline mosaic, or post-zygotic mutations, making segregation analysis inappropriate. Details ▾Hide ▴
Evidence considered
- VCEP specification: 'Not applicable as these are de novo
- germline mosaic or post-zygotic mutations.'
Sources
BP1 VCEPBP1 is designated as Not Applicable by the Brain Malformations VCEP v1.1; loss-of-function is not the disease mechanism for PIK3CA, so a missense variant in a gene where primarily truncating variants cause disease is not relevant. Details ▾Hide ▴
Evidence considered
- VCEP specification: 'Not applicable as LOF is not the disease mechanism.'
Sources
BP3 VCEPBP3 applies to in-frame deletions/insertions in repetitive regions without known function. NM_006218.4:c.1911+19G>T is a substitution, not an in-frame indel. Details ▾Hide ▴
Evidence considered
- Variant is a single nucleotide substitution
- not an in-frame indel.
BP6 VCEPBP6 is designated as Not Applicable by the Brain Malformations VCEP v1.1 per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. Additionally, this variant is absent from ClinVar. Details ▾Hide ▴
PS5 N/APS5 is not a criterion in the standard ACMG/AMP 2015 framework or in the Brain Malformations VCEP v1.1. The criterion commonly labeled PS5 (reputable source reports variant as pathogenic) is designated as PP5 in the standard framework. Details ▾Hide ▴
Evidence considered
- No PS5 criterion exists in ACMG/AMP 2015 or this VCEP.
Identifiers
- Gene
- PIK3CA
- Transcript
- NM_006218.4
- Coding (HGVS c.)
- NM_006218.4:c.1911+19G>T
- Protein (HGVS p.)
- NP_006209.2:p.?
- GRCh38
- chr3:179219754 G>T
- GRCh37
- chr3:178937542 G>T
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
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 BP4 under the Brain Malformations VCEP applies to intronic variants (except canonical splice sites) and requires two of three splicing prediction tools (varSEAK, SpliceAI, MaxEntScan) to predict no impact. SpliceAI predicts no impact (max delta score = 0.01), but varSEAK and MaxEntScan scores are unavailable. Criterion cannot be fully adjudicated with only one of three required tools. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.01 (no splice impact). VarSEAK and MaxEntScan scores not available.
Still missing
- Missing varSEAK and MaxEntScan splicing predictions
- need 2 of 3 tools to apply BP4 per VCEP specification.
Sources
BP7 BP7 under the Brain Malformations VCEP applies to intronic positions (except canonical splice sites) and requires the nucleotide to be non-conserved (PhyloP score < 0.1). PhyloP conservation score is not available for this variant position, preventing adjudication. Details ▾Hide ▴
Evidence considered
- Variant is intronic at c.1911+19
- not a canonical splice site. PhyloP conservation score not available for this genomic position.
Still missing
- PhyloP conservation score required for BP7 adjudication per VCEP specification.
Sources
PP3 VCEPPP3 is designated as Not Applicable by the Brain Malformations VCEP v1.1; traditional mutation pathogenicity prediction algorithms focus on loss-of-function mechanisms and are not validated for gain-of-function variants in PIK3CA. Details ▾Hide ▴
Evidence considered
- VCEP specification: 'Not applicable since these variants are GOF
- and traditional mutation pathogenicity prediction algorithms focus on LOF mechanisms.'
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
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 0.010
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/?term=NM_006218.4%3Ac.1911%2B19G%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-178937542-G-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-179219754-G-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/3-179219754-G-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006218.4%3Ac.1911…
- OncoKB ↗www.oncokb.org/gene/PIK3CA/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PIK3CA+c.1911+19G%3ET
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 = 0.01).
Somatic
This variant has not previously been reported in somatic cancers (COSMIC).