About PIK3CA
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PIK3CA c.112C>T, p.(Arg38Cys)
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: 1
Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is completely absent from all gnomAD population databases: gnomAD v2.1 (0/248,624 alleles), gnomAD v4.1 (0/1,611,102 alleles), and gnomAD-Canada v1.0. Per the Brain Malformations VCEP, PM2_Supporting is awarded when the variant is absent or rare (≤1) in ethnically-matched population cohorts.
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: PM2 supporting (+1) = 1 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
0 / 1,611,102 alleles
gnomAD v4.1: 0 / 1,611,102 alleles. Recorded AF 0. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/248624 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/15466 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.050 maximum delta
Recorded SpliceAI maximum delta score: 0.050. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
2 reported laboratory submissions
2 Uncertain significance.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
39 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV55874617, n = 39 times).
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.
26 criteria with recorded statuses: 1 met · 9 not met · 5 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
This variant is completely absent from population databases including gnomAD v2.1 (0/248,624 alleles) and gnomAD v4.1 (0/1,611,102 alleles), meeting PM2_Supporting per the Brain Malformations VCEP.
No other pathogenic or benign criteria are met under the Brain Malformations VCEP v1.1.0 framework. PVS1, PP3, PP4, PP5, BS4, PM6, BP1, BP4, BP6, BP7, and PP1 are explicitly not applicable per the VCEP. Most remaining criteria lack variant-specific evidence in the published literature.
OncoKB curates p.Arg38Cys as Likely Oncogenic with Likely Gain-of-function biological context; however, no variant-specific functional data was identified in the reviewed full-text publications, and the Brain Malformations VCEP PS3 criterion requires validated functional assays meeting specific quality metrics.
This variant has been reported in ClinVar as Uncertain significance by two clinical laboratories (ClinVarID 376493). No de novo reports, segregation data, or brain malformation phenotype cases were identified.
Variant has been observed in somatic cancers (COSMIC, n=39 occurrences) but this does not independently support germline brain malformation pathogenicity under the VCEP PS4 framework.
No criteria match.
Met · 1
PM2 SupportingThis variant is completely absent from all gnomAD population databases: gnomAD v2.1 (0/248,624 alleles), gnomAD v4.1 (0/1,611,102 alleles), and gnomAD-Canada v1.0. Per the Brain Malformations VCEP, PM2_Supporting is awarded when the variant is absent or rare (≤1) in ethnically-matched population cohorts. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 0/248
- 624 alleles
- gnomAD v4.1: 0/1
- 611
- 102 alleles
- gnomAD-Canada: absent.
Sources
Not met · 9 · evaluated, threshold not reached
PS1 No previously established pathogenic variant causing the same amino acid change (p.Arg38Cys) via a different nucleotide change was identified. The variant is absent from ClinVar pathogenic assertions and no literature reports a different nucleotide substitution producing p.Arg38Cys. Details ▾Hide ▴
Evidence considered
- ClinVar lists NM_006218.4:c.112C>T as Uncertain significance with no pathogenic entries at this residue via an alternate nucleotide change.
Sources
PM1 Residue Arg38 lies outside the Table 4 PIK3CA critical functional domains (kinase domain AA 322–483 and AA 797–1068) per the Brain Malformations VCEP. While Cancer Hotspots identifies residue 38 as statistically significant, the VCEP specifies PM1_Supporting based on domain membership, not hotspot recurrence. Residue 38 is in the p85-binding/adaptor-binding domain, which is not a Table 4 approved domain. Details ▾Hide ▴
Evidence considered
- VCEP Table 4 lists PIK3CA kinase domains at AA 322–483 and AA 797–1068
- Arg38 is outside these domains. Cancer Hotspots flags residue 38 as significant but VCEP PM1 is domain-based.
Sources
BA1 Variant is completely absent from all gnomAD populations (0/248,624 in v2.1, 0/1,611,102 in v4.1). The Brain Malformations VCEP BA1 threshold is allele frequency >0.0926%. The observed frequency of 0% does not meet this threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF=0%
- gnomAD v4.1 AF=0%
- VCEP BA1 threshold is >0.0926%.
Sources
BS1 Variant is completely absent from all gnomAD populations. The Brain Malformations VCEP BS1 threshold is allele frequency >0.0185%. The observed frequency of 0% does not meet this threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF=0%
- gnomAD v4.1 AF=0%
- VCEP BS1 threshold is >0.0185%.
Sources
BS2 No homozygotes present in gnomAD (0/248,624 in v2.1, 0/1,611,102 in v4.1) and no well-phenotyped heterozygous family members without disease have been reported. The VCEP requires ≥3 homozygotes in gnomAD or ≥3 heterozygous in well-phenotyped family members to award BS2_Strong. Details ▾Hide ▴
Evidence considered
- 0 homozygotes in gnomAD v2.1 and v4.1
- no published reports of unaffected heterozygous carriers.
Sources
BS3 No well-established in vitro or in vivo functional studies demonstrate a benign effect. OncoKB curates this variant as Likely Gain-of-function/Likely Oncogenic, which is consistent with a damaging effect rather than a benign one. Details ▾Hide ▴
Evidence considered
- OncoKB curates p.Arg38Cys as Likely Oncogenic with Likely Gain-of-function biological effect
- no functional study demonstrates a neutral or benign effect.
Sources
BP2 No evidence that this variant has been observed in cis or in trans with a known pathogenic variant in PIK3CA. No phase information is available from any reviewed source. Details ▾Hide ▴
Evidence considered
- No cis/trans phase data available in ClinVar
- literature
- or any reviewed source.
Still missing
- No phase or co-occurrence data available.
BP5 No evidence that this variant has been found in a case with an alternative molecular basis for disease. No publication or ClinVar submission describes this variant co-occurring with a confirmed pathogenic variant in another gene that fully explains the phenotype. Details ▾Hide ▴
Evidence considered
- No alternative molecular diagnosis reported in any case carrying this variant.
Still missing
- No data on alternative molecular diagnoses.
PS5 No reputable source reports this variant as pathogenic. ClinVar classification is Uncertain significance (2 clinical laboratories). OncoKB label of Likely Oncogenic is somatic-cancer context and does not constitute a germline diagnostic classification. Details ▾Hide ▴
Not assessed · 5 · no assessment recorded
PS2 No de novo observation of this variant has been identified in any reviewed publication or ClinVar submission. PS2 requires confirmed maternity/paternity with variant absent from parents (PS2_Strong) or at minimum satisfying one of the two VCEP criteria (PS2_Moderate). None of the available evidence supports a de novo event. Details ▾Hide ▴
Evidence considered
- Two ClinVar clinical testing submissions (GeneDx
- Invitae) list this variant as germline Uncertain significance but provide no de novo data or parental testing results.
Still missing
- No de novo reports available
- parental testing data not available.
Sources
PS3 No variant-specific functional data confirming a damaging effect was identified in any reviewed full-text publication. OncoKB curates this variant as Likely Oncogenic/Likely Gain-of-function, but no peer-reviewed functional study explicitly characterizing NM_006218.4:c.112C>T was found. The Brain Malformations VCEP requires functional assays meeting quality metrics per PMID:31892348 for PS3 application. Details ▾Hide ▴
Evidence considered
- OncoKB curates p.Arg38Cys as Likely Oncogenic with Likely Gain-of-function biological effect context
- however
- variant-specific experimental data in the published literature could not be independently verified in the full-text papers reviewed.
Still missing
- No variant-specific functional assay data in published literature
- OncoKB curation not independently confirmed.
Sources
PS4 No published cases of this variant in individuals with brain malformation phenotypes were identified in the reviewed literature. COSMIC reports 39 somatic cancer occurrences, but BMVCEP Table 2A assigns at most 0.25 points per tumor occurrence category, insufficient to achieve any PS4 strength level on its own. ClinVar clinical testing submissions provide no phenotypic detail. Details ▾Hide ▴
Evidence considered
- COSMIC reports 39 somatic occurrences
- ClinVar has 2 clinical submissions (VUS) without phenotype details
- no brain malformation cases identified in literature.
Still missing
- No published cases with brain malformation phenotypes
- PS4 requires phenotype points per VCEP Table 2A.
Sources
PM5 No pathogenic comparator variant at residue Arg38 was identified in ClinVar or the literature. PM5 requires a known pathogenic missense change at the same amino acid residue. The automated PM5 candidate search found no same-residue pathogenic variants and was classified as not_applicable due to insufficient comparator data. Without a confirmed pathogenic comparator at Arg38, PM5 cannot be evaluated. Details ▾Hide ▴
Evidence considered
- PM5 candidate search found 0 same-residue comparator variants at Arg38
- no pathogenic missense at Arg38 identified in ClinVar.
Still missing
- No pathogenic comparator variant at residue 38.
Sources
PP2 The Brain Malformations VCEP specifies PP2_Supporting for PIK3CA if the missense constraint z-score from ExAC/gnomAD exceeds 3.09. PIK3CA is known to be highly missense-constrained, but the specific gnomAD missense z-score was not available in the evidence brief for direct confirmation. Details ▾Hide ▴
Evidence considered
- VCEP specifies PP2 for PIK3CA when gnomAD missense z-score > 3.09. PIK3CA is known to have high missense constraint but the exact z-score was not captured in the evidence files.
Still missing
- Need to confirm gnomAD missense constraint z-score for PIK3CA exceeds 3.09.
Sources
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 VCEPNot applicable per Brain Malformations VCEP v1.1.0 — disease mechanism for PIK3CA is gain of function, not loss of function. Details ▾Hide ▴
Evidence considered
- CSPEC/Brain Malformations VCEP explicitly states PVS1 is not applicable for PIK3CA because the disease mechanism is gain of function.
Sources
PM6 VCEPNot applicable per Brain Malformations VCEP v1.1.0 — this criterion is addressed under PS2 and will not be used separately. Details ▾Hide ▴
Evidence considered
- CSPEC/Brain Malformations VCEP explicitly states PM6 is not applicable and is addressed under PS2.
Sources
PP1 VCEPNot applicable per Brain Malformations VCEP v1.1.0 — disease-causing variants in these genes are germline mosaic, de novo, or mosaic, making co-segregation analysis inapplicable. Details ▾Hide ▴
Evidence considered
- CSPEC/Brain Malformations VCEP explicitly states PP1 is not applicable because disease-causing variants are de novo or mosaic.
Sources
PP3 VCEPNot applicable per Brain Malformations VCEP v1.1.0 — traditional pathogenicity prediction algorithms focus on loss-of-function mechanisms, whereas PIK3CA variants act through gain of function. The VCEP explicitly states this criterion is not applicable until algorithms designed to detect GOF mutations are validated. Details ▾Hide ▴
Evidence considered
- CSPEC/Brain Malformations VCEP explicitly states PP3 is not applicable because computational predictors focus on LOF
- not GOF mechanisms.
Sources
PP4 VCEPNot applicable per Brain Malformations VCEP v1.1.0 — this criterion is accounted for under PS4. Details ▾Hide ▴
Evidence considered
- CSPEC/Brain Malformations VCEP states PP4 is not applicable since it is accounted for under PS4.
Sources
PP5 VCEPNot applicable per Brain Malformations VCEP v1.1.0 — this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
Evidence considered
- CSPEC/Brain Malformations VCEP explicitly states PP5 is not for use per ClinGen SVI VCEP Review Committee.
Sources
BS4 VCEPNot applicable per Brain Malformations VCEP v1.1.0 — these are de novo, germline mosaic, or post-zygotic mutations, making segregation analysis inapplicable. Details ▾Hide ▴
Evidence considered
- CSPEC/Brain Malformations VCEP explicitly states BS4 is not applicable.
Sources
BP1 VCEPNot applicable per Brain Malformations VCEP v1.1.0 — loss of function is not the disease mechanism for PIK3CA. Details ▾Hide ▴
Evidence considered
- CSPEC/Brain Malformations VCEP explicitly states BP1 is not applicable because LOF is not the disease mechanism.
Sources
BP4 N/ANot applicable per Brain Malformations VCEP v1.1.0 — BP4 is limited to synonymous, intronic (non-canonical splice), and UTR variants only. This variant is a missense substitution. Details ▾Hide ▴
Evidence considered
- VCEP BP4 specification is restricted to synonymous/intronic/UTR variants
- c.112C>T is a missense variant.
Sources
BP6 VCEPNot applicable per Brain Malformations VCEP v1.1.0 — this criterion is not for use as recommended by the ClinGen SVI VCEP Review Committee. Details ▾Hide ▴
Evidence considered
- CSPEC/Brain Malformations VCEP explicitly states BP6 is not for use per ClinGen SVI VCEP Review Committee.
Sources
BP7 N/ANot applicable per Brain Malformations VCEP v1.1.0 — BP7 is limited to synonymous, intronic (non-canonical splice), and UTR variants with PhyloP <0.1. This variant is a missense substitution. Details ▾Hide ▴
Evidence considered
- VCEP BP7 specification is restricted to synonymous/intronic/UTR variants
- c.112C>T is a missense variant.
Sources
Identifiers
- Gene
- PIK3CA
- Transcript
- NM_006218.4
- Coding (HGVS c.)
- NM_006218.4:c.112C>T
- Protein (HGVS p.)
- NP_006209.2:p.(Arg38Cys)
- GRCh38
- chr3:179198937 C>T
- GRCh37
- chr3:178916725 C>T
- ClinVar
- 376493
- COSMIC
- COSV55874617
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
0 / 1,611,102 alleles
AF 0 · 0 homozygotes
gnomAD v2.1
0 / 248,624 alleles
AF 0 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 0 · 0 / 1,611,102 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.
gnomAD v2.1
AF 0 · 0 / 248,624 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1611102 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/74900 alleles, homozygotes = 0).
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/248624 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/15466 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.737
- BayesDel
- 0.245
How the predictions were used
PP3 VCEPNot applicable per Brain Malformations VCEP v1.1.0 — traditional pathogenicity prediction algorithms focus on loss-of-function mechanisms, whereas PIK3CA variants act through gain of function. The VCEP explicitly states this criterion is not applicable until algorithms designed to detect GOF mutations are validated. Details ▾Hide ▴
Evidence considered
- CSPEC/Brain Malformations VCEP explicitly states PP3 is not applicable because computational predictors focus on LOF
- not GOF mechanisms.
Sources
BP4 N/ANot applicable per Brain Malformations VCEP v1.1.0 — BP4 is limited to synonymous, intronic (non-canonical splice), and UTR variants only. This variant is a missense substitution. Details ▾Hide ▴
Evidence considered
- VCEP BP4 specification is restricted to synonymous/intronic/UTR variants
- c.112C>T is a missense variant.
Sources
BP7 N/ANot applicable per Brain Malformations VCEP v1.1.0 — BP7 is limited to synonymous, intronic (non-canonical splice), and UTR variants with PhyloP <0.1. This variant is a missense substitution. Details ▾Hide ▴
Evidence considered
- VCEP BP7 specification is restricted to synonymous/intronic/UTR variants
- c.112C>T is a missense variant.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05). REVEL score = 0.737. BayesDel score = 0.244629.
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
-
PMID 29533785 ↗Systematic Functional Annotation of Somatic Mutations in Cancer.Reports a moderate-throughput functional genomic platform for systematic annotation of cancer somatic mutations using growth factor-dependent cell models and functional proteomic profiling. NM_006218.4:c.112C>T (p.Arg38Cys) was not identified in this paper.Does not name this variant
-
PMID 26122737 ↗Oncogenic mutations weaken the interactions that stabilize the p110α-p85α heterodimer in phosphatidylinositol 3-kinase α.Investigates how PI3K-alpha oncogenic mutations weaken p110-alpha/p85-alpha heterodimer interactions using biophysical and structural methods. NM_006218.4:c.112C>T (p.Arg38Cys) was not identified in this paper.Does not name this variant
-
PMID 28966033 ↗Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma.Integrated molecular meta-analysis of >1,000 pediatric high-grade and diffuse intrinsic pontine gliomas, identifying co-segregating mutations in histone-mutant subgroups. NM_006218.4:c.112C>T (p.Arg38Cys) was not identified in this paper.Does not name this variant
-
PMID 24705252 ↗Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma.Taylor KR et al. · 2014Reports recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma. NM_006218.4:c.112C>T (p.Arg38Cys) was not identified in this paper.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 Risk Assessment and Counseling summary; a general cancer genetics guideline. NM_006218.4:c.112C>T (p.Arg38Cys) was not identified in this source.Does not name this variant
-
PMID 26389333 ↗Genetics of Skin Cancer (PDQ®): Health Professional Version.PDQ Cancer Genetics Editorial Board · 2002PDQ Genetics of Skin Cancer summary; a general cancer genetics guideline. NM_006218.4:c.112C>T (p.Arg38Cys) was not identified in this source.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
0 / 1,611,102 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.050
Open source ↗
ClinVar
2 Uncertain significance
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/376493/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-178916725-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-179198937-C-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/3-179198937-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006218.4%3Ac.112C…
- OncoKB ↗www.oncokb.org/gene/PIK3CA/R38C
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=119880569
- 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
This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1611102 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/74900 alleles, homozygotes = 0).
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/248624 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/15466 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 376493)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05). REVEL score = 0.737. BayesDel score = 0.244629.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55874617, n = 39 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.