About PIK3CA
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PIK3CA c.1132T>C, p.(Cys378Arg)
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: 3
Benign evidence criteria: 0
Pathogenic criteria applied · 3
PM1Supporting
PM1 · supporting
Residue Cys378 lies within the PIK3CA amino acid 322-483 interval listed by the Brain Malformations VCEP as an approved critical functional domain for PM1_Supporting, so PM1 is met at supporting strength.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and gnomAD v4.1, with 0/1519490 alleles and 0 homozygotes in gnomAD v4.1; this is below the VCEP PM2 requirement for absent or rare variation in controls and supports PM2 at supporting strength.
PM5Moderate
PM5 · moderate
A different missense change at the same residue, PIK3CA p.Cys378Tyr, is reported in ClinVar as Pathogenic with multiple submitters and no conflicts. Because this variant is also a missense change at codon 378 and SpliceAI predicts no splice impact (max delta score 0.00), classic same-residue PM5 is supported at moderate strength.
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: PM1 supporting (+1) + PM2 supporting (+1) + PM5 moderate (+2) = 4 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 / 1,519,490 alleles
gnomAD v4.1: 0 / 1,519,490 alleles. Recorded AF 0. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
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
5 reported laboratory submissions
4 Pathogenic · 1 Likely pathogenic.
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
16 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV55882697, n = 16 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.
28 criteria with recorded statuses: 3 met · 4 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 c.1132T>C (p.Cys378Arg) variant has been reported in ClinVar with an overall Pathogenic classification, and curated somatic oncology resources also list this variant in cancer-associated context.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, including 0/1519490 alleles and 0 homozygotes in gnomAD v4.1, which supports rarity in population controls.
Curated functional literature links and a published PIK3CA study support a gain-of-function disease mechanism for mutant PIK3CA, but variant-specific assay evidence meeting Brain Malformations VCEP PS3 requirements was not established for p.Cys378Arg.
The variant lies in a Brain Malformations VCEP-approved PIK3CA functional domain, a different missense change at the same residue has been reported as pathogenic, and SpliceAI predicts no splice effect; REVEL and BayesDel scores are also elevated, although PP3 is not applied by this VCEP for gain-of-function missense variants.
No criteria match.
Met · 3
PM1 SupportingResidue Cys378 lies within the PIK3CA amino acid 322-483 interval listed by the Brain Malformations VCEP as an approved critical functional domain for PM1_Supporting, so PM1 is met at supporting strength. Details ▾Hide ▴
Rule
VCEP PM1_Supporting for variants in approved Table 4 domains.
Evidence considered
- PIK3CA Table 4 approved domain AA 322-483
- Variant protein consequence p.Cys378Arg
Sources
cspec ↗vcep_clingen_brainmalform_acmg_specifications_v1_1
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1, with 0/1519490 alleles and 0 homozygotes in gnomAD v4.1; this is below the VCEP PM2 requirement for absent or rare variation in controls and supports PM2 at supporting strength. Details ▾Hide ▴
Rule
VCEP PM2_Supporting for absent/rare variation in controls.
Evidence considered
- gnomAD v2.1 absent
- gnomAD v4.1 total AC 0 of 1519490 alleles
Sources
PM5 ModerateA different missense change at the same residue, PIK3CA p.Cys378Tyr, is reported in ClinVar as Pathogenic with multiple submitters and no conflicts. Because this variant is also a missense change at codon 378 and SpliceAI predicts no splice impact (max delta score 0.00), classic same-residue PM5 is supported at moderate strength. Details ▾Hide ▴
Rule
VCEP PM5 uses classic same-residue missense logic with no modification.
Evidence considered
- ClinVar same-residue comparator p.Cys378Tyr classified Pathogenic
- SpliceAI max delta score 0.00 for p.Cys378Arg
Still missing
- Independent expert-panel same-residue comparator data were not identified in the reviewed sources.
Sources
Not met · 4 · evaluated, threshold not reached
PS1 No alternate nucleotide change producing the same p.Cys378Arg amino acid substitution was identified in the reviewed ClinVar evidence, and SpliceAI predicts no splice effect that would complicate a protein-based comparison. Details ▾Hide ▴
Rule
VCEP PS1: same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Evidence considered
- ClinVar record for p.Cys378Arg only
- SpliceAI max delta score 0.00
Still missing
- A comprehensive codon-level search outside the reviewed ClinVar evidence was not assembled.
Sources
BA1 This variant does not meet BA1 because it is absent from gnomAD, with 0/1519490 alleles in gnomAD v4.1, which is below the VCEP BA1 threshold of greater than 0.0926%. Details ▾Hide ▴
Rule
VCEP BA1 threshold >0.0926%.
Evidence considered
- gnomAD v4.1 AF 0.0
- VCEP BA1 threshold >0.0926%
Sources
BS1 This variant does not meet BS1 because it is absent from gnomAD, with 0/1519490 alleles in gnomAD v4.1, which is below the VCEP BS1 threshold of greater than 0.0185%. Details ▾Hide ▴
Rule
VCEP BS1 threshold >0.0185%.
Evidence considered
- gnomAD v4.1 AF 0.0
- VCEP BS1 threshold >0.0185%
Sources
BS2 This variant does not meet BS2 because no homozygotes were observed in gnomAD v4.1, whereas the Brain Malformations VCEP requires at least 3 homozygotes in gnomAD or at least 3 well-phenotyped unaffected family observations. Details ▾Hide ▴
Rule
VCEP BS2 requires >=3 homozygotes in gnomAD or >=3 well-phenotyped unaffected family observations.
Evidence considered
- gnomAD v4.1 homozygotes 0
- VCEP BS2 threshold >=3 homozygotes or >=3 unaffected family observations
Still missing
- Well-phenotyped unaffected family data were not available.
Sources
Not assessed · 7 · no assessment recorded
PS2 No confirmed de novo or tissue-comparison data were identified to show this variant was absent from parental samples and enriched in affected tissue, so PS2 cannot be applied from the reviewed evidence. Details ▾Hide ▴
Rule
VCEP PS2 requires documented de novo or mosaic tissue-distribution evidence.
Evidence considered
- VCEP PS2 requires parental absence and/or tissue distribution evidence
- ClinVar and literature summaries did not provide case-level PS2 data
Still missing
- Parental testing results with confirmed maternity and paternity
- Cross-tissue allele fraction data
Sources
PS3 Curated literature links and a published PIK3CA functional study support a gain-of-function disease mechanism for PIK3CA variants, but variant-specific assay details meeting the Brain Malformations VCEP validation requirements were not established for p.Cys378Arg from the reviewed evidence. Details ▾Hide ▴
Rule
VCEP PS3 requires validated functional evidence meeting SVI/BMVCEP assay criteria.
Evidence considered
- OncoKB variant page identified curated functional literature
- PMID:17363507 described gain-of-function behavior for mutant PIK3CA in cell models
Still missing
- Direct variant-specific functional assay data for p.Cys378Arg
- Assay validation details required by the VCEP framework
Sources
PS4 This variant is rare enough to satisfy the PM2 prerequisite, but the reviewed evidence did not provide a consolidated phenotype-based point total under the Brain Malformations VCEP PS4 scoring system, so PS4 was not applied. Details ▾Hide ▴
Rule
VCEP PS4 is phenotype-point based and requires PM2 first.
Evidence considered
- PM2 prerequisite satisfied by absence from gnomAD
- ClinVar submissions indicate affected observations but not VCEP point totals
Still missing
- Case-level phenotype point assignment under Table 2A
- Total PS4 point sum across independent affected individuals
Sources
PP2 The Brain Malformations VCEP allows PP2 for PIK3CA missense variants when the gene-specific missense constraint threshold is exceeded, but a registered case-source record documenting that threshold assessment for this case was not included in the reviewed evidence, so PP2 was left unscored. Details ▾Hide ▴
Rule
VCEP PP2 for PIK3CA if missense z-score > 3.09.
Evidence considered
- VCEP PP2 rule requires missense constraint threshold assessment
Still missing
- Case-linked documentation of the gene missense constraint assessment
Sources
BS3 No well-established study demonstrating normal or non-damaging function for p.Cys378Arg was identified, so BS3 was not applied. Details ▾Hide ▴
Rule
VCEP BS3 requires validated functional evidence showing no damaging effect.
Evidence considered
- No reviewed evidence showed normal function for p.Cys378Arg
- Reviewed functional literature supported mutant PIK3CA gain-of-function context rather than benign effect
Still missing
- Variant-specific benign functional data meeting VCEP validation criteria
Sources
BP2 No phase information was identified showing this variant in cis or trans with another known pathogenic PIK3CA variant, so BP2 was not applied. Details ▾Hide ▴
BP5 No alternate molecular diagnosis was identified that would explain the phenotype independently of this variant, so BP5 was not applied. Details ▾Hide ▴
Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 VCEPPVS1 is not applicable in the Brain Malformations VCEP framework for PIK3CA because the disease mechanism is gain of function, and this variant is a missense substitution rather than a null variant. Details ▾Hide ▴
VCEP rule
VCEP PVS1 not applicable for PIK3CA gain-of-function disease.
Evidence considered
- VCEP marks PVS1 not applicable for PIK3CA
- Variant is missense
Sources
PM3 VCEPPM3 is not applicable in this Brain Malformations VCEP framework because PIK3CA-related disease is not interpreted as a recessive condition requiring trans observations. Details ▾Hide ▴
PM4 VCEPPM4 is not applicable in this Brain Malformations VCEP framework, and this variant is a missense substitution rather than a protein length-changing variant. Details ▾Hide ▴
VCEP rule
VCEP PM4 not applicable.
Evidence considered
- Variant is missense
- VCEP PM4 marked not applicable
Sources
PM6 VCEPPM6 is not used in this Brain Malformations VCEP framework because de novo evidence is handled under PS2. Details ▾Hide ▴
PP1 VCEPPP1 is not applicable in this Brain Malformations VCEP framework because PIK3CA-related cases are typically mosaic or de novo rather than interpreted through classic familial segregation. Details ▾Hide ▴
PP3 VCEPPP3 is not applicable in this Brain Malformations VCEP framework for PIK3CA gain-of-function missense variants. REVEL (0.817), BayesDel (0.273988), and SpliceAI (max delta score 0.00) were reviewed but were not used to score PP3 under this rule. Details ▾Hide ▴
VCEP rule
VCEP PP3 not applicable for GOF variants.
Evidence considered
- REVEL 0.817
- BayesDel 0.273988
- SpliceAI max delta score 0.00
Sources
PP4 VCEPPP4 is not applicable in this Brain Malformations VCEP framework because phenotype specificity is incorporated into the PS4 point-based system instead. Details ▾Hide ▴
PP5 VCEPPP5 is not used in this Brain Malformations VCEP framework. Details ▾Hide ▴
BS4 VCEPBS4 is not applicable in this Brain Malformations VCEP framework. Details ▾Hide ▴
BP1 VCEPBP1 is not applicable in this Brain Malformations VCEP framework because PIK3CA-related disease is mediated by gain of function rather than a predominantly truncating loss-of-function mechanism. Details ▾Hide ▴
BP3 VCEPBP3 is not applicable in this Brain Malformations VCEP framework, and this variant is not an in-frame insertion or deletion in a repetitive region. Details ▾Hide ▴
VCEP rule
VCEP BP3 not applicable.
Evidence considered
- VCEP BP3 marked not applicable
- Variant is missense
Sources
BP4 N/ABP4 is not applicable because this is a missense variant, and the Brain Malformations VCEP restricts BP4 to synonymous, intronic, or UTR variants evaluated for lack of splice impact. Details ▾Hide ▴
Rule
VCEP BP4 applies only to synonymous, intronic, or UTR variants with negative splicing predictions.
Evidence considered
- Variant is missense
- VCEP BP4 restricted to synonymous/intronic/UTR variants
Sources
BP6 VCEPBP6 is not used in this Brain Malformations VCEP framework. Details ▾Hide ▴
BP7 N/ABP7 is not applicable because this is a missense variant rather than a synonymous or intronic change. Details ▾Hide ▴
Rule
VCEP BP7 applies only to synonymous, intronic, or UTR variants.
Evidence considered
- Variant is missense
- VCEP BP7 restricted to synonymous/intronic/UTR variants
Sources
Identifiers
- Gene
- PIK3CA
- Transcript
- NM_006218.4
- Coding (HGVS c.)
- NM_006218.4:c.1132T>C
- Protein (HGVS p.)
- NP_006209.2:p.(Cys378Arg)
- GRCh38
- chr3:179204575 T>C
- GRCh37
- chr3:178922363 T>C
- ClinVar
- 917489
- COSMIC
- COSV55882697
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 / 1,519,490 alleles
AF 0 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 0 · 0 / 1,519,490 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%, 0/1519490 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/73306 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.817
- BayesDel
- 0.274
How the predictions were used
PP3 VCEPPP3 is not applicable in this Brain Malformations VCEP framework for PIK3CA gain-of-function missense variants. REVEL (0.817), BayesDel (0.273988), and SpliceAI (max delta score 0.00) were reviewed but were not used to score PP3 under this rule. Details ▾Hide ▴
VCEP rule
VCEP PP3 not applicable for GOF variants.
Evidence considered
- REVEL 0.817
- BayesDel 0.273988
- SpliceAI max delta score 0.00
Sources
BP4 N/ABP4 is not applicable because this is a missense variant, and the Brain Malformations VCEP restricts BP4 to synonymous, intronic, or UTR variants evaluated for lack of splice impact. Details ▾Hide ▴
Rule
VCEP BP4 applies only to synonymous, intronic, or UTR variants with negative splicing predictions.
Evidence considered
- Variant is missense
- VCEP BP4 restricted to synonymous/intronic/UTR variants
Sources
BP7 N/ABP7 is not applicable because this is a missense variant rather than a synonymous or intronic change. Details ▾Hide ▴
Rule
VCEP BP7 applies only to synonymous, intronic, or UTR variants.
Evidence considered
- Variant is missense
- VCEP BP7 restricted to synonymous/intronic/UTR variants
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.817. BayesDel score = 0.273988.
14 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 17363507 ↗Colon carcinoma cells harboring PIK3CA mutations display resistance to growth factor deprivation induced apoptosis.No paper-specific finding is recorded.
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PMID 23619275 ↗ACMG position statement on prenatal/preconception expanded carrier screening.No paper-specific finding is recorded.
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PMID 23652378 ↗A framework to start the debate on neonatal screening policies in the EU: an Expert Opinion Document.No paper-specific finding is recorded.
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PMID 25626707 ↗Whole-genome sequencing in newborn screening? A statement on the continued importance of targeted approaches in newborn screening programmes.No paper-specific finding is recorded.
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PMID 25730230 ↗Expanded carrier screening in reproductive medicine-points to consider: a joint statement of the American College of Medical Genetics and Genomics, American College of Obstetricians and Gynecologists, National Society of Genetic Counselors, Perinatal Quality Foundation, and Society for Maternal-Fetal Medicine.No paper-specific finding is recorded.
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PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.No paper-specific finding is recorded.
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PMID 31585106 ↗Diagnostic Utility of Next-Generation Sequencing for Disorders of Somatic Mosaicism: A Five-Year Cumulative Cohort.McNulty SN et al. · 2019No paper-specific finding is recorded.
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PMID 33105631 ↗Somatic Variant Analysis Identifies Targets for Tailored Therapies in Patients with Vascular Malformations.Paolacci S et al. · 2020No paper-specific finding is recorded.
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PMID 22947299 ↗Specific guidelines for assessing and improving the methodological quality of economic evaluations of newborn screening.No paper-specific finding is recorded.
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PMID 23037933 ↗Including the initial newborn screening bloodspot collection device serial number on birth certificates: basis and recommendations from the Secretary of Health and Human Services' Advisory Committee on Heritable Disorders in Newborns and Children.No paper-specific finding is recorded.
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PMID 23881473 ↗Newborn screening: education, consent, and the residual blood spot. The position of the national society of genetic counselors.No paper-specific finding is recorded.
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PMID 24022298 ↗Offering prenatal diagnostic tests: European guidelines for clinical practice [corrected].No paper-specific finding is recorded.
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PMID 24394680 ↗Parental permission for pilot newborn screening research: guidelines from the NBSTRN.No paper-specific finding is recorded.
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PMID 31022120 ↗ACOG Committee Opinion No. 778 Summary: Newborn Screening and the Role of the Obstetrician-Gynecologist.No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
0 / 1,519,490 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
4 Pathogenic · 1 Likely pathogenic
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/917489/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-178922363-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-179204575-T-C?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006218.4%3Ac.1132…
- OncoKB ↗www.oncokb.org/gene/PIK3CA/C378R
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=108144042
- 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%, 0/1519490 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/73306 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Pathogenic (4 clinical laboratories) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 917489)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.817. BayesDel score = 0.273988.
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; COSV55882697, n = 16 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.