About PIK3CA
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PIK3CA c.2937-15T>C, 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
145 / 1,586,692 alleles
gnomAD v4.1: 145 / 1,586,692 alleles. Recorded AF 9.13851e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 6.25732e-05; MAF= 0.00626%, 17/271682 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000117495; MAF= 0.01175%, 4/34044 alleles, homozygotes = 0); grpmax FAF= 5.237e-05.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.00021715526601520088, 4/18420 alleles, homozygotes = 0).
No listed criterion applied
SpliceAI score
0.170 maximum delta
Recorded SpliceAI maximum delta score: 0.170. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
1 reported laboratory submissions
1 Likely benign. ClinVar API review status: criteria provided, single submitter.
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 · 13 not met · 0 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
NM_006218.4:c.2937-15T>C is an intronic variant in PIK3CA located 15 bases upstream of exon 20.
PVS1 is not applicable per the ClinGen Brain Malformations VCEP v1.1.0: the disease mechanism for PIK3CA-related brain malformations is gain of function, not loss of function.
This variant is present in 17 individuals (0.00626% AF) in gnomAD v2.1 and 145 individuals (0.00914% AF) in gnomAD v4.1, exceeding the VCEP PM2 threshold of at most one individual.
No pathogenic criteria are met and most are not applicable due to the intronic nature of the variant or explicit VCEP exclusion. No benign criteria are met. The classification falls within the VUS range (0 to 5 points) under the Brain Malformations Tavtigian point framework.
No criteria match.
Not met · 13 · evaluated, threshold not reached
PS2 No de novo evidence is available for NM_006218.4:c.2937-15T>C. The VCEP requires either confirmed de novo with tissue mosaicism (PS2_Strong) or confirmed de novo without tissue data (PS2_Moderate). Neither criterion is satisfied by currently available evidence. Details ▾Hide ▴
Evidence considered
- No de novo reports found in ClinVar
- literature
- or other sources for this variant.
Still missing
- No parental testing or tissue-specific mosaicism data available.
PS3 No well-established in vitro or in vivo functional studies are available for NM_006218.4:c.2937-15T>C. No functional data were identified in OncoKB, COSMIC, or the reviewed literature. The VCEP requires functional assays meeting SVI quality metrics (PMID:31892348); no qualifying studies exist for this variant. Details ▾Hide ▴
Evidence considered
- No functional data identified in OncoKB
- COSMIC
- or literature.
Still missing
- No functional studies published for this intronic variant.
Sources
PS4 No affected individuals with brain malformation phenotypes have been reported for NM_006218.4:c.2937-15T>C in the reviewed literature. The VCEP PS4 framework requires phenotypic case counting via Table 2A and is contingent on PM2 being met. Neither PM2 nor any case-level evidence is satisfied. Details ▾Hide ▴
Evidence considered
- No patients reported with this variant in ClinVar or the reviewed literature
- no case-level phenotypic data available.
Still missing
- No case reports or cohort data for this variant in brain malformation patients.
Sources
PM1 PM1_Supporting per the VCEP requires the variant to affect a residue within a critical functional domain listed in Table 4 (for PIK3CA: kinase domain AA 322-483 or kinase domain AA 797-1068). NM_006218.4:c.2937-15T>C is an intronic variant located 15 bases upstream of exon 20; it does not alter or reside within a coding amino acid and therefore does not affect a residue in an approved functional domain. Details ▾Hide ▴
Evidence considered
- Variant is intronic (c.2937-15 in intron 20)
- does not map to a coding residue in either PIK3CA kinase domain (AA 322-483 or AA 797-1068).
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
PM2 VCEP PM2_Supporting requires the variant to be absent or rare from controls with at most one individual (≤1) in an ethnically-matched cohort. NM_006218.4:c.2937-15T>C is observed in 17 individuals in gnomAD v2.1 and 145 individuals in gnomAD v4.1, far exceeding the one-person threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 17/271
- 682 alleles (AF 0.00626%)
- gnomAD v4.1: 145/1
- 586
- 692 alleles (AF 0.00914%)
- exceeds VCEP PM2 ≤1 person threshold.
Sources
BA1 VCEP BA1 requires an allele frequency above 0.0926%. NM_006218.4:c.2937-15T>C has a maximum observed population frequency of 0.01175% (Admixed American, gnomAD v2.1) and 0.01154% (European non-Finnish, gnomAD v4.1), both well below the BA1 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 max sub-pop AF: 0.01175% (AMR)
- gnomAD v4.1 max sub-pop AF: 0.01154% (NFE). Both below 0.0926% BA1 threshold.
Sources
BS1 VCEP BS1 requires an allele frequency above 0.0185%. NM_006218.4:c.2937-15T>C has a maximum observed population frequency of 0.01175% (gnomAD v2.1 AMR), which is below the 0.0185% threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 max sub-pop AF: 0.01175% (AMR) — below 0.0185% BS1 threshold
- gnomAD v4.1 max sub-pop AF: 0.01154% (NFE).
Sources
BS2 VCEP BS2 requires ≥3 homozygotes in gnomAD or ≥3 heterozygous individuals in well-phenotyped family members. NM_006218.4:c.2937-15T>C has zero homozygotes in gnomAD v2.1 and v4.1, and no well-phenotyped family member data are available. Details ▾Hide ▴
Evidence considered
- 0 homozygotes in gnomAD v2.1 and v4.1
- no well-phenotyped family data available.
Still missing
- No family-based phenotyping data.
Sources
BS3 No well-established in vitro or in vivo functional studies demonstrate a neutral effect for NM_006218.4:c.2937-15T>C. The VCEP requires functional assays meeting SVI quality metrics (PMID:31892348); no qualifying benign functional studies exist for this variant. Details ▾Hide ▴
Evidence considered
- No functional data demonstrating neutral effect identified in OncoKB
- COSMIC
- or literature.
Still missing
- No functional studies published for this intronic variant.
Sources
BP2 BP2 requires observation of the variant in cis or trans with a known pathogenic variant in the same gene. No phasing data or co-occurrence with a known pathogenic PIK3CA variant has been reported for NM_006218.4:c.2937-15T>C. Details ▾Hide ▴
Evidence considered
- No cis/trans phasing data available for this variant.
Still missing
- No phasing data or co-occurrence reports with known pathogenic PIK3CA variants.
BP4 VCEP BP4 applies to intronic positions (except canonical splice sites) and requires two of three splicing prediction tools (varSEAK, SpliceAI, MaxEntScan) to predict no impact on splicing. SpliceAI predicts no significant splice impact (max delta = 0.17), but varSEAK and MaxEntScan data are unavailable. With only one of three tools available, the two-of-three threshold is not met. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.17 (no significant splice impact)
- only 1 of 3 required tools available.
Still missing
- varSEAK and MaxEntScan scores not available
- cannot satisfy VCEP two-of-three requirement.
Sources
BP5 BP5 requires the variant to be found in a case with an alternate molecular basis for disease. No evidence of an alternate molecular diagnosis co-occurring with NM_006218.4:c.2937-15T>C is available. Details ▾Hide ▴
Evidence considered
- No reports of this variant co-occurring with an alternate molecular diagnosis.
Still missing
- No case data with alternate molecular basis available.
BP7 VCEP BP7 applies to intronic positions (except canonical splice sites) and requires the nucleotide to be non-conserved (PhyloP score <0.1). A PhyloP conservation score is not available for this position. Without the PhyloP score, the criterion cannot be applied. Details ▾Hide ▴
Evidence considered
- PhyloP score not available for c.2937-15 position
- cannot determine conservation status.
Still missing
- PhyloP conservation score needed for BP7 assessment.
Sources
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 VCEPPVS1 is not applicable per the ClinGen Brain Malformations VCEP v1.1.0: the disease mechanism for PIK3CA-related brain malformations is gain of function; loss of function and/or haploinsufficiency have not been identified as disease mechanisms. Details ▾Hide ▴
Evidence considered
- VCEP explicitly states PVS1 is not applicable — disease mechanism is gain of function.
Sources
cspec ↗final_classification_framework
PS1 N/APS1 requires the same amino acid change as a previously established pathogenic variant regardless of nucleotide change. NM_006218.4:c.2937-15T>C is an intronic variant that does not alter an amino acid; PS1 cannot be applied to non-coding variants. Details ▾Hide ▴
Evidence considered
- Intronic variant at c.2937-15 does not produce an amino acid change
- which is a prerequisite for PS1.
PM5 N/APM5 applies to novel missense changes at an amino acid residue where a different pathogenic missense change has been observed. NM_006218.4:c.2937-15T>C is an intronic variant with no amino acid consequence; the pm5_candidates pipeline confirms the variant class is not missense-like. Details ▾Hide ▴
Evidence considered
- pm5_candidates pipeline confirms not eligible: variant class is not missense-like
- no amino acid residue context available.
Sources
pm5_candidates
PM6 VCEPPM6 is not applicable per the ClinGen Brain Malformations VCEP: this criterion is subsumed under PS2 and is not used independently. Details ▾Hide ▴
Evidence considered
- VCEP states PM6 is addressed according to PS2 and will not be used.
Sources
PP1 VCEPPP1 is not applicable per the ClinGen Brain Malformations VCEP: disease-causing variants in PIK3CA-related brain malformations are germline mosaic, de novo, or mosaic; co-segregation analysis is not relevant. Details ▾Hide ▴
Evidence considered
- VCEP states PP1 is not applicable since disease-causing variants are de novo or mosaic.
Sources
PP2 N/APP2 is designed for missense variants in genes with low rates of benign missense variation (measured via missense constraint Z-score). NM_006218.4:c.2937-15T>C is an intronic variant and the PP2 missense constraint framework does not apply to non-coding variants. Details ▾Hide ▴
Evidence considered
- PP2 criterion is predicated on missense constraint
- not applicable to intronic variants.
Sources
PP3 VCEPPP3 is not applicable per the ClinGen Brain Malformations VCEP: traditional pathogenicity prediction algorithms focus on loss-of-function mechanisms and are not designed for gain-of-function variants in PIK3CA. Details ▾Hide ▴
Evidence considered
- VCEP explicitly states PP3 is not applicable since variants are GOF and traditional algorithms focus on LOF mechanisms.
Sources
PP4 VCEPPP4 is not applicable per the ClinGen Brain Malformations VCEP: this criterion is accounted for under PS4. Details ▾Hide ▴
Evidence considered
- VCEP states PP4 is not applicable since this criterion is accounted for under PS4.
Sources
PP5 VCEPPP5 is not applicable per the ClinGen Brain Malformations VCEP: this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
Evidence considered
- VCEP states PP5 is not for use per ClinGen SVI VCEP Review Committee.
Sources
BS4 VCEPBS4 is not applicable per the ClinGen Brain Malformations VCEP: disease-causing variants in PIK3CA-related brain malformations are de novo, germline mosaic, or post-zygotic mutations; segregation analysis is not applicable. Details ▾Hide ▴
Evidence considered
- VCEP states BS4 is not applicable as these are de novo
- germline mosaic or post-zygotic mutations.
Sources
BP1 VCEPBP1 is not applicable per the ClinGen Brain Malformations VCEP: the disease mechanism for PIK3CA is gain of function; loss of function is not the disease mechanism, so the principle that primarily truncating variants cause disease does not apply. Details ▾Hide ▴
Evidence considered
- VCEP states BP1 is not applicable as LOF is not the disease mechanism.
Sources
BP6 VCEPBP6 is not applicable per the ClinGen Brain Malformations VCEP: this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
Evidence considered
- VCEP states BP6 is not for use per ClinGen SVI VCEP Review Committee.
Sources
PS5 N/APS5 applies to novel missense changes at an amino acid residue where a different pathogenic missense change has been established. NM_006218.4:c.2937-15T>C is an intronic variant that does not alter an amino acid; no amino acid residue is affected. Details ▾Hide ▴
Evidence considered
- Intronic variant does not involve an amino acid residue
- prerequisite for PS5 not satisfied.
Identifiers
- Gene
- PIK3CA
- Transcript
- NM_006218.4
- Coding (HGVS c.)
- NM_006218.4:c.2937-15T>C
- Protein (HGVS p.)
- NP_006209.2:p.?
- GRCh38
- chr3:179234079 T>C
- GRCh37
- chr3:178951867 T>C
- ClinVar
- 1602491
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
145 / 1,586,692 alleles
AF 9.14e-05 · 0 homozygotes · FAF 9.94e-05
gnomAD v2.1
17 / 271,682 alleles
AF 6.26e-05 · 0 homozygotes · FAF 5.24e-05
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 9.1e-05 · 145 / 1,586,692 alleles · 0 hom · FAF 9.9e-05
| European (non-Finnish)134 / 1,160,924 | 0.00012 |
| Ashkenazi Jewish3 / 28,698 | 0.0001 |
| Admixed American3 / 58,596 | 5.1e-05 |
| Remaining individuals3 / 61,278 | 4.9e-05 |
| African/African American2 / 74,156 | 2.7e-05 |
0 alternate alleles recorded in 5 other groups: European (Finnish), Amish, East Asian, Middle Eastern, South Asian.
gnomAD v2.1
AF 6.3e-05 · 17 / 271,682 alleles · 0 hom · FAF 5.2e-05
| Admixed American4 / 34,044 | 0.00012 |
| Ashkenazi Jewish1 / 9,542 | 0.0001 |
| European (non-Finnish)12 / 125,156 | 9.6e-05 |
0 alternate alleles recorded in 5 other groups: African/African American, East Asian, European (Finnish), Remaining individuals, South Asian.
gnomAD-Canada
AF not recorded · ? / ? alleles
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 9.13851e-05; MAF= 0.00914%, 145/1586692 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000115425; MAF= 0.01154%, 134/1160924 alleles, homozygotes = 0); grpmax FAF= 9.935e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 6.25732e-05; MAF= 0.00626%, 17/271682 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000117495; MAF= 0.01175%, 4/34044 alleles, homozygotes = 0); grpmax FAF= 5.237e-05.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.00021715526601520088, 4/18420 alleles, homozygotes = 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 VCEP BP4 applies to intronic positions (except canonical splice sites) and requires two of three splicing prediction tools (varSEAK, SpliceAI, MaxEntScan) to predict no impact on splicing. SpliceAI predicts no significant splice impact (max delta = 0.17), but varSEAK and MaxEntScan data are unavailable. With only one of three tools available, the two-of-three threshold is not met. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.17 (no significant splice impact)
- only 1 of 3 required tools available.
Still missing
- varSEAK and MaxEntScan scores not available
- cannot satisfy VCEP two-of-three requirement.
Sources
BP7 VCEP BP7 applies to intronic positions (except canonical splice sites) and requires the nucleotide to be non-conserved (PhyloP score <0.1). A PhyloP conservation score is not available for this position. Without the PhyloP score, the criterion cannot be applied. Details ▾Hide ▴
Evidence considered
- PhyloP score not available for c.2937-15 position
- cannot determine conservation status.
Still missing
- PhyloP conservation score needed for BP7 assessment.
Sources
PP3 VCEPPP3 is not applicable per the ClinGen Brain Malformations VCEP: traditional pathogenicity prediction algorithms focus on loss-of-function mechanisms and are not designed for gain-of-function variants in PIK3CA. Details ▾Hide ▴
Evidence considered
- VCEP explicitly states PP3 is not applicable since variants are GOF and traditional algorithms focus on LOF mechanisms.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.17).
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. · 2013Clinical genetics guideline for evaluating the etiology of autism spectrum disorders. Discusses chromosomal microarray, fragile X, MECP2, and PTEN testing strategies. Does not mention PIK3CA or NM_006218.4:c.2937-15T>C.Does not name this variant
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PMID 25190698 ↗Genetic/familial high-risk assessment: breast and ovarian, version 1.2014.Daly MB et al. · 2014NCCN guidelines for genetic/familial high-risk assessment of breast and ovarian cancer. Focuses on BRCA1/BRCA2, TP53, and PTEN. Discusses Cowden syndrome diagnostic criteria. Does not mention PIK3CA or NM_006218.4:c.2937-15T>C.Does not name this variant
-
PMID 26389210 ↗Genetics of Breast and Gynecologic Cancers (PDQ®): Health Professional Version.PDQ Cancer Genetics Editorial Board · 2002PDQ cancer genetics summary on genetics of breast and gynecologic cancers. General overview of hereditary cancer syndromes. Does not mention PIK3CA or NM_006218.4:c.2937-15T>C.Does not name this variant
-
PMID 26389258 ↗Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.PDQ Cancer Genetics Editorial Board · 2002PDQ cancer genetics summary on cancer genetics risk assessment and counseling. General overview. Does not mention PIK3CA or NM_006218.4:c.2937-15T>C.Does not name this variant
-
PMID 26389333 ↗Genetics of Skin Cancer (PDQ®): Health Professional Version.PDQ Cancer Genetics Editorial Board · 2002PDQ cancer genetics summary on genetics of skin cancer. General overview. Does not mention PIK3CA or NM_006218.4:c.2937-15T>C.Does not name this variant
-
PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017Sherloc refinement of the ACMG-AMP variant classification criteria. A methodological framework paper cited by Labcorp Genetics (Invitae) as the basis for their Likely benign classification of this variant in ClinVar. Does not contain variant-specific evidence for NM_006218.4:c.2937-15T>C.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
145 / 1,586,692 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.170
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/1602491/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-178951867-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-179234079-T-C?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/3-179234079-T-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006218.4%3Ac.2937…
- OncoKB ↗www.oncokb.org/gene/PIK3CA/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PIK3CA+c.2937-15T%3EC
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= 9.13851e-05; MAF= 0.00914%, 145/1586692 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000115425; MAF= 0.01154%, 134/1160924 alleles, homozygotes = 0); grpmax FAF= 9.935e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 6.25732e-05; MAF= 0.00626%, 17/271682 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000117495; MAF= 0.01175%, 4/34044 alleles, homozygotes = 0); grpmax FAF= 5.237e-05.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.00021715526601520088, 4/18420 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Likely benign (1 clinical laboratory). (ClinVarID = 1602491)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.17).
Somatic
This variant has not previously been reported in somatic cancers (COSMIC).