About PIK3CA
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PIK3CA c.2782C>T, p.(Gln928Ter)
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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM1Supporting
PM1 · supporting
This variant truncates PIK3CA at p.(Gln928Ter), which lies within the PIK3CA kinase domain approved by the Brain Malformations VCEP for PM1_Supporting (amino acids 797-1068). This location is within a critical functional domain, so PM1 is met at supporting strength.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed allele count is 0, which is within the Brain Malformations VCEP PM2_Supporting threshold of at most 1 occurrence in population data. PM2 is met at supporting strength.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
Generic ACMG/AMP final classification combination rules were used as fallback because the retrieved Brain Malformations Specification final-classification framework was present but not complete for direct application.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
No listed criterion applied
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB oncogenicity for this specific variant: Unknown Oncogenic Effect (variant has not been individually curated).
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Cancer Hotspots
This variant does not lie 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: 2 met · 5 not met · 5 not assessed · 16 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.2782C>T (p.Gln928Ter; p.Q928*) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is within the Brain Malformations VCEP PM2_Supporting threshold of at most 1 occurrence in population data and below the BS1 (>0.0185%) and BA1 (>0.0926%) thresholds.
The variant lies within the PIK3CA kinase domain approved for PM1_Supporting by the Brain Malformations VCEP (amino acids 797-1068), supporting location in a critical functional region.
SpliceAI predicts no significant splice impact for this variant with a maximum delta score of 0.10, although PP3 and BP4 are not applicable to this nonsense variant under the Brain Malformations VCEP specifications.
No criteria match.
Met · 2
PM1 SupportingThis variant truncates PIK3CA at p.(Gln928Ter), which lies within the PIK3CA kinase domain approved by the Brain Malformations VCEP for PM1_Supporting (amino acids 797-1068). This location is within a critical functional domain, so PM1 is met at supporting strength. Details ▾Hide ▴
Rule
A supporting point may be awarded if the variant of interest is located in an exon within one of the approved functional domains in Table 4.
Evidence considered
- The Brain Malformations VCEP allows PM1 at supporting strength for variants in approved functional domains.
- Table 4 lists a PIK3CA kinase domain spanning amino acids 797-1068.
- The variant protein consequence is p.(Gln928Ter)/p.(Q928*).
Sources
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed allele count is 0, which is within the Brain Malformations VCEP PM2_Supporting threshold of at most 1 occurrence in population data. PM2 is met at supporting strength. Details ▾Hide ▴
Rule
Absent/rare from controls in an ethnically-matched cohort population sample (≤1); this criterion has been downgraded to supporting.
Evidence considered
- PM2_Supporting applies when the variant is absent or rare in controls, with one person maximum.
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
Sources
Not met · 5 · evaluated, threshold not reached
PS1 This nonsense variant results in p.(Gln928Ter), but no previously established pathogenic variant with the same amino acid change was identified. ClinVar contains no entry for this variant and no literature reports were identified, so PS1 is not met. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Evidence considered
- PS1 requires the same amino acid change as a previously established pathogenic variant.
- This variant is absent from ClinVar.
- No PMIDs were identified across retrieved evidence sources.
Still missing
- Additional case-level or database evidence showing the same amino acid change as an established pathogenic variant would be needed.
Sources
BS2 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so it does not meet the VCEP BS2 threshold of at least 3 homozygotes in population data. No well-phenotyped unaffected family members carrying the variant were identified. Details ▾Hide ▴
Rule
Award BS2 if ≥3 homozygotes present in gnomAD or ≥3 heterozygous in well phenotyped family members.
Evidence considered
- BS2 requires at least 3 homozygotes in gnomAD or at least 3 heterozygous well-phenotyped family members.
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
Still missing
- Well-phenotyped unaffected carrier data were not available.
Sources
PS4 This variant is absent from gnomAD and therefore satisfies the population prerequisite for PS4 consideration, but no phenotype-based case evidence was identified to contribute PS4 points. The variant was not found in COSMIC, is absent from ClinVar, and no literature reports were identified, so PS4 is not met. Details ▾Hide ▴
Rule
Points are assigned for phenotype according to Table 2A and converted to strength by Table 2B; phenotype criteria can only be used if the variant is absent/rare from controls according to PM2.
Evidence considered
- PS4 requires phenotype-based point scoring and can only be used if PM2 is met.
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
- This variant has not previously been reported in somatic cancers (COSMIC).
- This variant is absent from ClinVar.
- No PMIDs were identified across retrieved evidence sources.
Still missing
- No phenotype-specific published cases or case-level observations were identified for PS4 point scoring.
Sources
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed allele frequency is 0, which is below the Brain Malformations VCEP BA1 threshold of greater than 0.0926%. BA1 is not met. Details ▾Hide ▴
Rule
Allele frequency (>0.0926%).
Evidence considered
- BA1 requires allele frequency greater than 0.0926%.
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
Sources
BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed allele frequency is 0, which is below the Brain Malformations VCEP BS1 threshold of greater than 0.0185%. BS1 is not met. Details ▾Hide ▴
Rule
Allele frequency (>0.0185%).
Evidence considered
- BS1 requires allele frequency greater than 0.0185%.
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
Sources
Not assessed · 5 · no assessment recorded
PS2 No case-specific parental testing or multi-tissue allele fraction data were identified. Available evidence therefore does not allow assessment of the Brain Malformations VCEP PS2 de novo/mosaic criteria. Details ▾Hide ▴
Rule
Award PS2_Strong if Criteria 1 and Criteria 2 are fulfilled; award PS2_Moderate if Criteria 1 is fulfilled, or if parents are unavailable but Criteria 2 is fulfilled.
Evidence considered
- PS2 requires parental absence and/or tissue distribution evidence under the VCEP framework.
- No PMIDs were identified across retrieved evidence sources.
Still missing
- Confirmed maternity and paternity data were not available.
- Affected-tissue versus unaffected-tissue allele fraction data were not available.
Sources
cspec ↗literature_pass
BP5 No evidence was identified showing that this variant was observed in an individual with an alternate molecular basis for disease in a different gene. BP5 therefore could not be assessed from the available evidence. Details ▾Hide ▴
Rule
Observed in a case with an alternate molecular basis for disease in a different gene.
Evidence considered
- BP5 requires an alternate molecular basis for disease.
- No PMIDs were identified across retrieved evidence sources.
Still missing
- Case-level data addressing alternative molecular diagnoses were not available.
Sources
cspec ↗literature_pass
BP2 No evidence was identified showing that this variant was observed in cis or trans with a known pathogenic variant in PIK3CA. BP2 therefore could not be assessed from the available evidence. Details ▾Hide ▴
Rule
Observed in cis or trans with a known pathogenic variant in the same gene.
Evidence considered
- BP2 requires observation in cis or trans with a known pathogenic variant in the same gene.
- No PMIDs were identified across retrieved evidence sources.
Still missing
- Phase information and second-variant data were not available.
Sources
cspec ↗literature_pass
BS3 No well-established functional studies showing no damaging effect for this specific variant were identified. BS3 could not be assessed from the available evidence. Details ▾Hide ▴
Rule
Follow recommendations set forth by the SVI in conjunction with specifications added by the Brain Malformation Group for quality metrics and minimum validation controls required.
Evidence considered
- BS3 requires well-established functional evidence showing no damaging effect.
- No PMIDs were identified across retrieved evidence sources.
Still missing
- Variant-specific benign functional data meeting VCEP quality requirements were not available.
Sources
cspec ↗literature_pass
PS3 No well-established functional studies supporting a damaging effect for this specific variant were identified. PS3 could not be assessed from the available evidence. Details ▾Hide ▴
Rule
Award PS3 only when functional assays meet the acceptability criteria delimited in PMID:31892348 with BMVCEP specifications.
Evidence considered
- PS3 requires well-established functional studies meeting VCEP/SVI quality criteria.
- No PMIDs were identified across retrieved evidence sources.
Still missing
- Variant-specific functional data meeting Brain Malformations VCEP assay requirements were not available.
Sources
cspec ↗literature_pass
Not applicable · 16· recorded as not applicable Show reasons ▾Hide reasons ▴
BS4 N/ABS4 is not applicable under the Brain Malformations VCEP because these disorders are interpreted in the context of de novo, germline mosaic, or post-zygotic variants rather than lack of segregation in affected relatives. Details ▾Hide ▴
Rule
Not applicable as these are de novo, germline mosaic or post-zygotic mutations.
Evidence considered
- The Brain Malformations VCEP marks BS4 as not applicable.
Sources
PP4 N/APP4 is not applicable under the Brain Malformations VCEP because phenotype specificity is incorporated into the PS4 point-based framework. Details ▾Hide ▴
Rule
Not applicable since this criterion is accounted for under PS4.
Evidence considered
- The Brain Malformations VCEP marks PP4 as not applicable.
Sources
PP3 N/APP3 is not applicable under the Brain Malformations VCEP because these disorders are primarily interpreted as gain-of-function conditions, and the specification states that traditional pathogenicity prediction algorithms are not used for this criterion. Details ▾Hide ▴
Rule
This criterion is not applicable since these variants are GOF, and traditional mutation pathogenicity prediction algorithms focus on LOF mechanisms.
Evidence considered
- The Brain Malformations VCEP marks PP3 as not applicable for these genes.
- SpliceAI predicts no significant splice impact for this variant with a maximum delta score of 0.10.
Sources
PVS1 N/AAlthough this is a nonsense variant, PVS1 is not applicable under the Brain Malformations VCEP because the specification states that loss of function is not the established disease mechanism for these genes and that the relevant disease mechanism is gain of function. The generic PVS1 scaffold was not used because official VCEP rules take precedence. Details ▾Hide ▴
Rule
LOF and/or haploinsufficiency have not been clearly identified as disease mechanisms underlying brain malformations related to these genes, so in general this rule is not applicable.
Evidence considered
- The Brain Malformations VCEP marks PVS1 as not applicable.
- The variant is a nonsense change, p.(Gln928Ter)/p.(Q928*).
- A generic PVS1 scaffold was generated, but framework precedence is CSPEC/VCEP first.
Sources
PP5 N/APP5 is not applicable because the ClinGen SVI VCEP Review Committee does not recommend use of this criterion. Details ▾Hide ▴
Rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
- The Brain Malformations VCEP marks PP5 as not applicable.
Sources
BP7 N/ABP7 is limited to synonymous, intronic non-canonical splice, or UTR variants with low conservation. This variant is a nonsense coding change, so BP7 is not applicable. Details ▾Hide ▴
Rule
For synonymous, intronic positions (except canonical splice sites) and non-coding variants in the UTRs, if the nucleotide is non-conserved award this point.
Evidence considered
- BP7 under the VCEP applies to synonymous, intronic, or UTR variants.
- The variant is a nonsense coding change, p.(Gln928Ter)/p.(Q928*).
Sources
BP4 N/ABP4 under this VCEP is restricted to synonymous, intronic non-canonical splice, or UTR variants when at least 2 of 3 splicing tools predict no splicing impact. Although SpliceAI predicts no significant splice effect with a maximum delta score of 0.10, this variant is a nonsense coding change, so BP4 is not applicable. Details ▾Hide ▴
Rule
Not applicable for any variant type except for synonymous, intronic positions (except canonical splice sites) and non-coding variants in the UTRs.
Evidence considered
- BP4 is not applicable for variant types other than synonymous, intronic non-canonical splice, or UTR variants.
- SpliceAI predicts no significant splice impact with a maximum delta score of 0.10.
- The variant is a nonsense coding change, p.(Gln928Ter)/p.(Q928*).
Sources
BP3 N/ABP3 is not applicable under the Brain Malformations VCEP because these genes do not have approved repetitive regions without known function for use of this criterion. Details ▾Hide ▴
Rule
This is not applicable for the genes specified since the exon regions do not have repetitive regions without a known function.
Evidence considered
- The Brain Malformations VCEP marks BP3 as not applicable.
Sources
BP1 N/ABP1 is not applicable under the Brain Malformations VCEP because loss of function is not the disease mechanism for these genes. Details ▾Hide ▴
Rule
Not applicable as LOF is not the disease mechanism.
Evidence considered
- The Brain Malformations VCEP marks BP1 as not applicable.
Sources
PP2 N/APP2 applies to missense variants in genes with missense constraint. This variant is a nonsense change rather than a missense variant, so PP2 is not applicable. Details ▾Hide ▴
Rule
Award PP2 if the z-score > 3.09 for missense variants in applicable genes.
Evidence considered
- PP2 applies to missense variants.
- The variant is a nonsense coding change, p.(Gln928Ter)/p.(Q928*).
Sources
PP1 N/APP1 is not applicable under the Brain Malformations VCEP because disease-causing variants in this framework are typically germline mosaic, de novo, or mosaic rather than segregating through multiple affected relatives. Details ▾Hide ▴
Rule
Not applicable since disease-causing variants are germline mosaic, de novo or mosaic.
Evidence considered
- The Brain Malformations VCEP marks PP1 as not applicable.
Sources
PM5 N/APM5 is restricted to a novel missense change at a residue where a different pathogenic missense change has been observed. This variant is a nonsense change, so PM5 is not applicable. Details ▾Hide ▴
Rule
Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
Evidence considered
- PM5 applies to missense changes.
- The variant is a nonsense coding change, p.(Gln928Ter)/p.(Q928*).
Sources
PM4 N/APM4 is not applicable under the Brain Malformations VCEP for these genes. This criterion is reserved for in-frame insertions/deletions or stop-loss variants and is not used in this framework. Details ▾Hide ▴
Rule
Although rare in-frame indels may occur, this point will still not be used in this framework.
Evidence considered
- The Brain Malformations VCEP marks PM4 as not applicable.
Sources
PM3 N/APM3 is not applicable under the Brain Malformations VCEP because the relevant disease-causing variants are interpreted as heterozygous rather than recessive biallelic variants. Details ▾Hide ▴
Rule
Not applicable since disease-causing variants are heterozygous.
Evidence considered
- The Brain Malformations VCEP marks PM3 as not applicable.
Sources
BP6 N/ABP6 is not applicable because the ClinGen SVI VCEP Review Committee does not recommend use of this criterion. Details ▾Hide ▴
Rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
- The Brain Malformations VCEP marks BP6 as not applicable.
Sources
PM6 N/APM6 is not applicable under the Brain Malformations VCEP because de novo evidence is addressed through PS2 rather than PM6. Details ▾Hide ▴
Rule
This point is addressed according to PS2 and will not be used.
Evidence considered
- The Brain Malformations VCEP marks PM6 as not applicable.
Sources
Identifiers
- Gene
- PIK3CA
- Transcript
- NM_006218.4
- Coding (HGVS c.)
- NM_006218.4:c.2782C>T
- Protein (HGVS p.)
- NP_006209.2:p.(Gln928Ter)
- GRCh38
- chr3:179230119 C>T
- GRCh37
- chr3:178947907 C>T
Gene diagram
Every interpreted variant in PIK3CA, mapped onto the exon structure of NM_006218.4. Select a row to find it on the plot.
PIK3CANM_006218.4
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in PIK3CA
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 N/APP3 is not applicable under the Brain Malformations VCEP because these disorders are primarily interpreted as gain-of-function conditions, and the specification states that traditional pathogenicity prediction algorithms are not used for this criterion. Details ▾Hide ▴
Rule
This criterion is not applicable since these variants are GOF, and traditional mutation pathogenicity prediction algorithms focus on LOF mechanisms.
Evidence considered
- The Brain Malformations VCEP marks PP3 as not applicable for these genes.
- SpliceAI predicts no significant splice impact for this variant with a maximum delta score of 0.10.
Sources
BP7 N/ABP7 is limited to synonymous, intronic non-canonical splice, or UTR variants with low conservation. This variant is a nonsense coding change, so BP7 is not applicable. Details ▾Hide ▴
Rule
For synonymous, intronic positions (except canonical splice sites) and non-coding variants in the UTRs, if the nucleotide is non-conserved award this point.
Evidence considered
- BP7 under the VCEP applies to synonymous, intronic, or UTR variants.
- The variant is a nonsense coding change, p.(Gln928Ter)/p.(Q928*).
Sources
BP4 N/ABP4 under this VCEP is restricted to synonymous, intronic non-canonical splice, or UTR variants when at least 2 of 3 splicing tools predict no splicing impact. Although SpliceAI predicts no significant splice effect with a maximum delta score of 0.10, this variant is a nonsense coding change, so BP4 is not applicable. Details ▾Hide ▴
Rule
Not applicable for any variant type except for synonymous, intronic positions (except canonical splice sites) and non-coding variants in the UTRs.
Evidence considered
- BP4 is not applicable for variant types other than synonymous, intronic non-canonical splice, or UTR variants.
- SpliceAI predicts no significant splice impact with a maximum delta score of 0.10.
- The variant is a nonsense coding change, p.(Gln928Ter)/p.(Q928*).
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10).
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
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/?term=NM_006218.4%3Ac.2782C%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-178947907-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-179230119-C-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006218.4%3Ac.2782…
- OncoKB ↗www.oncokb.org/gene/PIK3CA/Q928*
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PIK3CA+c.2782C%3ET
- 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
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10).
Functional
OncoKB oncogenicity for this specific variant: Unknown Oncogenic Effect (variant has not been individually curated).
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.