About PIK3CA
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PIK3CA c.2016-11G>A, 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 v1.1.0. 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: 0
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
Brain Malformations Specification Tavtigian point framework v1.1.0 point-based framework: no point-contributing criteria = 0 points, 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
71 / 1,580,816 alleles
gnomAD v4.1: 71 / 1,580,816 alleles. Recorded AF 4.49135e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 2.66622e-05; MAF= 0.00267%, 7/262544 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 6.43501e-05; MAF= 0.00644%, 2/31080 alleles, homozygotes = 0); grpmax FAF= 1.277e-05.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
No listed criterion applied
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
1 reported laboratory submissions
1 Likely benign.
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 v1.1.0, with the data and sources behind each one.
26 criteria with recorded statuses: 0 met · 11 not met · 1 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
NM_006218.4:c.2016-11G>A is an intronic variant in PIK3CA (intron 13, 11 bases upstream of exon 13). The variant has been observed at low frequency in population databases: 7/262,544 alleles in gnomAD v2.1 (AF 0.00267%) and 71/1,580,816 alleles in gnomAD v4.1 (AF 0.00449%), with no homozygotes.
SpliceAI predicts no splicing impact (max delta score = 0.00), suggesting the intronic nucleotide substitution does not create or disrupt a splice site.
This variant has been reported in ClinVar as Likely benign by a single clinical laboratory (Labcorp Genetics, SCV002406335) with review status 'criteria provided, single submitter.' No expert panel classifications are available.
No functional studies, case reports, segregation data, or de novo observations have been published for this variant. All six associated ClinVar PMIDs are general practice guidelines or background reviews with no variant-specific evidence.
Under the Brain Malformations VCEP (v1.1.0) Tavtigian point framework, no pathogenic criteria are met and no benign criteria are met. The total point score is 0, which falls within the VUS range (0 to 5 points).
Multiple benign-suggesting criteria (BP4, BP7) could not be fully assessed due to missing computational data (varSEAK, MaxEntScan, PhyloP). If additional splicing prediction tools confirm no impact and PhyloP indicates low conservation, this variant may be reclassified toward likely benign.
No criteria match.
Not met · 11 · evaluated, threshold not reached
PS2 No de novo observations have been reported for this variant. PS2 requires demonstration of the variant at detectable allele fraction in an affected tissue, absent from parental samples. No such evidence is available. Details ▾Hide ▴
Evidence considered
- No de novo reports identified in ClinVar or literature
Still missing
- No parental or tissue-specific allele fraction data available
PS3 No well-established in vitro or in vivo functional studies have been performed for this variant. SpliceAI predicts no splicing impact (max delta = 0.00), but this alone does not constitute functional evidence of a damaging effect per VCEP PS3 requirements. Details ▾Hide ▴
Evidence considered
- SpliceAI delta 0.00 (no splicing impact predicted)
- No variant-specific functional studies available
Still missing
- No functional assays (phosphorylation
- DEPTOR binding
- cell proliferation
- or animal models) performed for this variant
Sources
PS4 No affected individuals with this variant have been reported in the literature or ClinVar with phenotype data suitable for VCEP Table 2A point assignment. PS4 requires PM2 first and case-level phenotype documentation; neither is satisfied. Details ▾Hide ▴
Evidence considered
- ClinVar classification Likely benign by single submitter
- no phenotype-rich case reports
- No literature cases identified for this variant
Still missing
- No published case reports with phenotype data for this variant
Sources
PM2 This variant is present in gnomAD at frequencies exceeding the VCEP PM2 threshold of ≤1 individual. gnomAD v2.1: 7 alleles (AF 0.00267%); gnomAD v4.1: 71 alleles (AF 0.00449%). The variant is not absent or sufficiently rare to meet PM2_Supporting. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 7/262544 alleles (AF=0.00267%
- 0 homozygotes)
- gnomAD v4.1: 71/1580816 alleles (AF=0.00449%
Sources
BA1 The allele frequency in gnomAD (0.0045% in v4.1) is well below the VCEP BA1 threshold of >0.0926%. The variant is too rare in population databases to apply the stand-alone benign criterion. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 AF=0.00449% is below BA1 threshold (>0.0926%)
- gnomAD v2.1 AF=0.00267% is below BA1 threshold
Sources
BS1 The allele frequency in gnomAD (0.0045% in v4.1) is below the VCEP BS1 threshold of >0.0185%. The variant does not meet the strong benign population frequency criterion. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 AF=0.00449% is below BS1 threshold (>0.0185%)
- gnomAD v2.1 AF=0.00267% is below BS1 threshold
Sources
BS2 No homozygotes are present in gnomAD (0 in both v2.1 and v4.1), and no well-phenotyped heterozygous family members have been reported. The VCEP requires ≥3 homozygotes or ≥3 heterozygous in well-phenotyped family members. Details ▾Hide ▴
Evidence considered
- gnomAD homozygotes: 0
- No phenotyped family data available
Still missing
- No family segregation or phenotype data
Sources
BS3 No well-established in vitro or in vivo functional studies have been performed demonstrating no damaging effect on protein function or splicing for this variant. Details ▾Hide ▴
Evidence considered
- No variant-specific functional studies available
Still missing
- No functional assays performed for this intronic variant
BP2 No evidence is available indicating this variant has been observed in cis or trans with a known pathogenic variant in PIK3CA. Details ▾Hide ▴
Evidence considered
- No phase data available for this variant
Still missing
- No cis/trans phase information with known pathogenic PIK3CA variants
BP5 No evidence is available indicating this variant was found in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Evidence considered
- No alternate molecular diagnosis identified for carriers of this variant
Still missing
- No clinical data on alternate molecular diagnoses in carriers
BP7 This intronic variant is eligible for BP7 per VCEP rules, but no PhyloP conservation score is available to determine whether the nucleotide is non-conserved (PhyloP < 0.1 required). Without this data, the criterion cannot be met. Details ▾Hide ▴
Evidence considered
- Intronic variant at c.2016-11 (eligible variant type)
- PhyloP score not available
Still missing
- PhyloP conservation score needed to assess nucleotide conservation
Not assessed · 1 · no assessment recorded
BP4 This intronic variant is eligible for BP4 assessment per VCEP rules, and SpliceAI predicts no splicing impact (max delta = 0.00). However, the VCEP requires two out of three splicing prediction tools (varSEAK, SpliceAI, MaxEntScan) to predict no impact. Only SpliceAI data is available; varSEAK and MaxEntScan scores are absent. The criterion cannot be fully adjudicated without the remaining two tools. Details ▾Hide ▴
Evidence considered
- SpliceAI delta = 0.00 (no splicing impact predicted)
- varSEAK and MaxEntScan data unavailable
Still missing
- varSEAK score needed
- MaxEntScan score needed
Sources
Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 VCEPNot applicable per the Brain Malformations VCEP: the disease mechanism for PIK3CA is gain of function (GOF), and LOF/haploinsufficiency has not been clearly identified as a disease mechanism underlying brain malformations. Details ▾Hide ▴
PS1 N/AThis intronic variant (c.2016-11G>A) does not produce an amino acid change; PS1 requires the same amino acid change as a previously established pathogenic variant. Details ▾Hide ▴
Evidence considered
- Intronic variant with no amino acid consequence
PM1 N/AThis intronic variant (c.2016-11G>A) does not encode an amino acid residue and therefore cannot be mapped to the VCEP Table 4 critical functional domains (kinase domain AA 322-483 or AA 797-1068). PM1 assesses protein domain location. Details ▾Hide ▴
PM5 N/AThis intronic variant does not produce a missense change. PM5 requires a novel missense change at an amino acid residue where a different pathogenic missense change has been previously observed. Details ▾Hide ▴
Evidence considered
- Intronic variant
- no amino acid change
- pm5_candidates confirms ineligible
PM6 VCEPNot applicable per the Brain Malformations VCEP: this criterion is addressed under PS2 and is not used independently. Details ▾Hide ▴
PP1 VCEPNot applicable per the Brain Malformations VCEP: disease-causing variants in these genes are germline mosaic, de novo, or mosaic, making co-segregation analysis inapplicable. Details ▾Hide ▴
PP2 N/APP2 applies to missense variants in genes with low rates of benign missense variation. This is an intronic variant and does not qualify for missense constraint assessment. Details ▾Hide ▴
Evidence considered
- Intronic variant
- not a missense change
PP3 VCEPNot applicable per the Brain Malformations VCEP: these variants are gain of function, and traditional mutation pathogenicity prediction algorithms focus on loss of function mechanisms. Details ▾Hide ▴
PP4 VCEPNot applicable per the Brain Malformations VCEP: this criterion is accounted for under PS4. Details ▾Hide ▴
PP5 VCEPNot applicable per the Brain Malformations VCEP: this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
BS4 VCEPNot applicable per the Brain Malformations VCEP: these are de novo, germline mosaic, or post-zygotic mutations, making segregation analysis inapplicable. Details ▾Hide ▴
BP1 VCEPNot applicable per the Brain Malformations VCEP: loss of function is not the disease mechanism for PIK3CA (gain of function). Details ▾Hide ▴
BP6 VCEPNot applicable per the Brain Malformations VCEP: this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
PS5 N/APS5 is not a recognized criterion in the ACMG/AMP 2015 framework or the Brain Malformations VCEP specification. Details ▾Hide ▴
Evidence considered
- Not a valid ACMG/AMP criterion
Identifiers
- Gene
- PIK3CA
- Transcript
- NM_006218.4
- Coding (HGVS c.)
- NM_006218.4:c.2016-11G>A
- Protein (HGVS p.)
- NP_006209.2:p.?
- GRCh38
- chr3:179220975 G>A
- GRCh37
- chr3:178938763 G>A
- ClinVar
- 1597494
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
71 / 1,580,816 alleles
AF 4.49e-05 · 0 homozygotes · FAF 4.49e-05
gnomAD v2.1
7 / 262,544 alleles
AF 2.67e-05 · 0 homozygotes · FAF 1.28e-05
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 4.5e-05 · 71 / 1,580,816 alleles · 0 hom · FAF 4.5e-05
| European (non-Finnish)65 / 1,163,904 | 5.6e-05 |
| Admixed American3 / 55,214 | 5.4e-05 |
| Remaining individuals2 / 60,936 | 3.3e-05 |
| South Asian1 / 84,924 | 1.2e-05 |
0 alternate alleles recorded in 6 other groups: European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 2.7e-05 · 7 / 262,544 alleles · 0 hom · FAF 1.3e-05
| Admixed American2 / 31,080 | 6.4e-05 |
| European (non-Finnish)5 / 121,974 | 4.1e-05 |
0 alternate alleles recorded in 6 other groups: African/African American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 4.49135e-05; MAF= 0.00449%, 71/1580816 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.58465e-05; MAF= 0.00558%, 65/1163904 alleles, homozygotes = 0); grpmax FAF= 4.489e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 2.66622e-05; MAF= 0.00267%, 7/262544 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 6.43501e-05; MAF= 0.00644%, 2/31080 alleles, homozygotes = 0); grpmax FAF= 1.277e-05.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP7 This intronic variant is eligible for BP7 per VCEP rules, but no PhyloP conservation score is available to determine whether the nucleotide is non-conserved (PhyloP < 0.1 required). Without this data, the criterion cannot be met. Details ▾Hide ▴
Evidence considered
- Intronic variant at c.2016-11 (eligible variant type)
- PhyloP score not available
Still missing
- PhyloP conservation score needed to assess nucleotide conservation
BP4 This intronic variant is eligible for BP4 assessment per VCEP rules, and SpliceAI predicts no splicing impact (max delta = 0.00). However, the VCEP requires two out of three splicing prediction tools (varSEAK, SpliceAI, MaxEntScan) to predict no impact. Only SpliceAI data is available; varSEAK and MaxEntScan scores are absent. The criterion cannot be fully adjudicated without the remaining two tools. Details ▾Hide ▴
Evidence considered
- SpliceAI delta = 0.00 (no splicing impact predicted)
- varSEAK and MaxEntScan data unavailable
Still missing
- varSEAK score needed
- MaxEntScan score needed
Sources
PP3 VCEPNot applicable per the Brain Malformations VCEP: these variants are gain of function, and traditional mutation pathogenicity prediction algorithms focus on loss of function mechanisms. Details ▾Hide ▴
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
6 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
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PMID 23519317 ↗Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions.Schaefer GB et al. · 2013ACMG practice guideline on clinical genetics evaluation for autism spectrum disorders. Discusses diagnostic yields of chromosomal microarray, fragile X testing, MECP2, and PTEN in ASD cohorts. NM_006218.4:c.2016-11G>A was not identified in this paper.Does not name this variant
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PMID 26389210 ↗Genetics of Breast and Gynecologic Cancers (PDQ®): Health Professional Version.PDQ Cancer Genetics Editorial Board · 2002PDQ cancer genetics summary on breast and gynecologic cancers. General background resource with no variant-specific data. NM_006218.4:c.2016-11G>A was not identified.Does not name this variant
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PMID 26389258 ↗Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.PDQ Cancer Genetics Editorial Board · 2002PDQ cancer genetics summary on risk assessment and counseling. General background resource with no variant-specific data. NM_006218.4:c.2016-11G>A was not identified.Does not name this variant
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PMID 26389333 ↗Genetics of Skin Cancer (PDQ®): Health Professional Version.PDQ Cancer Genetics Editorial Board · 2002PDQ cancer genetics summary on skin cancer. General background resource with no variant-specific data. NM_006218.4:c.2016-11G>A was not identified.Does not name this variant
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PMID 26389505 ↗Genetics of Colorectal Cancer (PDQ®): Health Professional Version.PDQ Cancer Genetics Editorial Board · 2002PDQ cancer genetics summary on colorectal cancer. General background resource with no variant-specific data. NM_006218.4:c.2016-11G>A was not identified.Does not name this variant
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017Describes the Sherloc variant classification framework, a refinement of ACMG-AMP criteria. Provides general classification methodology without variant-specific data. NM_006218.4:c.2016-11G>A was not identified.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
71 / 1,580,816 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
1 Likely benign
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/1597494/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-178938763-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-179220975-G-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/3-179220975-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006218.4%3Ac.2016…
- OncoKB ↗www.oncokb.org/gene/PIK3CA/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PIK3CA+c.2016-11G%3EA
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= 4.49135e-05; MAF= 0.00449%, 71/1580816 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.58465e-05; MAF= 0.00558%, 65/1163904 alleles, homozygotes = 0); grpmax FAF= 4.489e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 2.66622e-05; MAF= 0.00267%, 7/262544 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 6.43501e-05; MAF= 0.00644%, 2/31080 alleles, homozygotes = 0); grpmax FAF= 1.277e-05.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Likely benign (1 clinical laboratory). (ClinVarID = 1597494)
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).