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PIK3CAc.3203dupNot classified
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Variant interpretation report

PIK3CA c.3203dup, p.(Asn1068LysfsTer5)

NM_006218.4:c.3203dup NP_006209.2:p.(Asn1068LysfsTer5) View identifiers
Classification
Not classified

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. Select a step to read what it means.

Not classified yet.Select a step to read what it means.

In plain language

Gene-level background from the recorded interpretation.

About PIK3CA

No gene-level summary was recorded for this case.

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

The Brain Malformations VCEP specifies PM1 at Supporting strength for residues affecting critical functional domains listed in Table 4. The normalized protein consequence is p.(Asn1068LysfsTer5), and Table 4 for PIK3CA includes a domain spanning amino acids 797-1068, placing residue 1068 within the listed critical region.

PM2Supporting
PM2 · supporting

The variant was absent from both gnomAD v2.1 and gnomAD v4.1 in the assembled workspace, satisfying the Brain Malformations VCEP PM2 requirement for absence/rarity in controls at Supporting strength.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Not classified

Brain Malformations Specification final-classification framework from final_classification_framework (cspec_ruleset extract); framework_mode=unstructured_ruleset and framework_complete=false, so no clean VCEP final combination rule was available to convert the adjudicated criteria into a definitive class.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

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 classifies this variant as Likely Oncogenic; biological effect: Likely Gain-of-function.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed

No COSMIC evidence statement is recorded in this case.

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 · 3 not met · 6 not assessed · 17 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

The PIK3CA c.3203dup (p.Asn1068LysfsTer5; p.N1068Kfs*5) variant has been observed in somatic cancers in COSMIC (COSV55878665, 29 occurrences) and has also been reported in ClinVar as Likely pathogenic with criteria provided by a single submitter.

The variant was absent from both gnomAD v2.1 and gnomAD v4.1, supporting PM2 at the Brain Malformations VCEP supporting level and arguing against BA1, BS1, and BS2 population-based benign evidence.

The affected residue lies at Asn1068, and the Brain Malformations specification Table 4 lists a PIK3CA critical domain spanning amino acids 797-1068, supporting PM1_Supporting; however, although OncoKB and the literature triage point to likely gain-of-function biology, the workspace does not provide variant-specific validated assay details sufficient to adjudicate PS3.

SpliceAI predicts no significant splice impact for this variant (max delta score 0.03), but PP3 is not applicable in this gain-of-function VCEP and BP4/BP7 are restricted to synonymous, intronic, or UTR contexts rather than coding frameshift variants.

Met · 2

PM1 SupportingThe Brain Malformations VCEP specifies PM1 at Supporting strength for residues affecting critical functional domains listed in Table 4. The normalized protein consequence is p.(Asn1068LysfsTer5), and Table 4 for PIK3CA includes a domain spanning amino acids 797-1068, placing residue 1068 within the listed critical region. Details ▾Hide ▴
Rule
Residues affecting critical functional domains provided in Table 4 for each gene.
Evidence considered
  • Protein consequence p.(Asn1068LysfsTer5) / p.(N1068Kfs*5)
  • BMVCEP Table 4 PIK3CA domain AA 797-1068
Sources
output/prefetch.json:protein consequencevcep_db/PIK3CA/files/clingen_brainmalform_acmg_specifications_v1_1.pdf:Table 4vcep_db/PIK3CA/criteria.json:PM1
PM2 SupportingThe variant was absent from both gnomAD v2.1 and gnomAD v4.1 in the assembled workspace, satisfying the Brain Malformations VCEP PM2 requirement for absence/rarity in controls at Supporting strength. Details ▾Hide ▴
Rule
Absent/rare from controls in an ethnically-matched cohort population sample (≤1).
Evidence considered
  • Absent from gnomAD v2.1
  • Absent from gnomAD v4.1
Sources
output/evidence.json:gnomad.GNOMAD_V2_1output/evidence.json:gnomad.GNOMAD_V4_1vcep_db/PIK3CA/criteria.json:PM2

Not met · 3 · evaluated, threshold not reached

BA1 The VCEP BA1 threshold is >0.0926%, but the variant was absent from both gnomAD v2.1 and v4.1, so BA1 is not met. Details ▾Hide ▴
Rule
Allele frequency >0.0926%.
Evidence considered
  • Absent from gnomAD v2.1
  • Absent from gnomAD v4.1
Sources
output/evidence.json:gnomad.GNOMAD_V2_1output/evidence.json:gnomad.GNOMAD_V4_1vcep_db/PIK3CA/criteria.json:BA1
BS1 The VCEP BS1 threshold is >0.0185%, but the variant was absent from both gnomAD v2.1 and v4.1, so BS1 is not met. Details ▾Hide ▴
Rule
Allele frequency >0.0185%.
Evidence considered
  • Absent from gnomAD v2.1
  • Absent from gnomAD v4.1
Sources
output/evidence.json:gnomad.GNOMAD_V2_1output/evidence.json:gnomad.GNOMAD_V4_1vcep_db/PIK3CA/criteria.json:BS1
BS2 BS2 requires at least 3 homozygotes in gnomAD or at least 3 well-phenotyped heterozygous family members. The workspace shows absence from gnomAD and provides no qualifying healthy-family observations. Details ▾Hide ▴
Rule
Award BS2 if ≥3 homozygotes present in gnomAD or ≥3 heterozygotes in well phenotyped family members.
Evidence considered
  • Absent from gnomAD v2.1
  • Absent from gnomAD v4.1
  • No healthy family-member dataset in workspace
Sources
output/evidence.json:gnomadvcep_db/PIK3CA/criteria.json:BS2

Not assessed · 6 · no assessment recorded

PS2 The VCEP requires parental absence and/or tissue mosaic distribution data for PS2. The workspace contains no parental testing results and no affected-vs-unaffected tissue allele-fraction data for this case. Details ▾Hide ▴
Rule
PS2_Strong requires Criteria 1 and 2; PS2_Moderate requires Criteria 1 or, if parents unavailable, Criteria 2.
Evidence considered
  • No case-level parental or tissue mosaic evidence was assembled in the reviewed workspace
Still missing
  • Confirmed maternity and paternity data
  • Tissue-specific allele fraction comparison
Sources
vcep_db/PIK3CA/criteria.json:PS2output/case_summary.json
PS3 The workspace includes OncoKB annotation and flags PMID:29533785 as a functional paper, but it does not provide variant-specific assay results or enough assay-validation detail to confirm that PS3 requirements under the Brain Malformations VCEP/PMID:31892348 framework are met. Details ▾Hide ▴
Rule
Award PS3 only when functional assays meet SVI/BMVCEP validation requirements.
Evidence considered
  • OncoKB: Likely Oncogenic; biological effect Likely Gain-of-function
  • PMID 29533785 triaged as relevant functional literature
Still missing
  • Variant-specific functional assay result for c.3203dup / p.N1068Kfs*5
  • Assay validation/control details required by the VCEP functional framework
Sources
output/evidence.json:oncokboutput/literature_pass.json:PMID 29533785vcep_db/PIK3CA/criteria.json:PS329533785
PS4 The VCEP uses a phenotype-point system for PS4 and requires PM2 first. PM2 is supportable here, but the workspace does not provide pointable case-level phenotype data from the cited germline reports, so a PS4 strength cannot be assigned from the assembled materials alone. Details ▾Hide ▴
Rule
PS4 strength is determined by phenotype points and can only be used if the variant meets PM2.
Evidence considered
  • ClinVar reports the variant as Likely pathogenic
  • PMIDs 23946963 and 27631024 were triaged as case-observation literature
  • Variant absent from gnomAD v2.1 and v4.1
Still missing
  • Case-level phenotype scoring from VCEP Table 2A
  • Count of qualifying reported affected individuals for this exact variant
Sources
vcep_db/PIK3CA/criteria.json:PS4output/evidence.json:clinvaroutput/literature_pass.json:PMIDs 23946963 and 27631024output/evidence.json:gnomad2394696327631024
BS3 No well-established benign functional study for this exact variant is documented in the workspace. Available functional annotations instead point toward likely oncogenic/gain-of-function behavior, but the materials are not detailed enough for a formal benign BS3 assessment. Details ▾Hide ▴
Rule
Apply BS3 only with well-established studies showing no damaging effect.
Evidence considered
  • OncoKB: Likely Oncogenic; likely Gain-of-function
  • PMID 29533785 triaged as functional literature
Still missing
  • Variant-specific functional study showing no damaging effect
  • Assay validation details meeting VCEP/SVI standards
Sources
output/evidence.json:oncokboutput/literature_pass.json:PMID 29533785vcep_db/PIK3CA/criteria.json:BS329533785
BP2 BP2 could apply if the variant were observed in cis or trans with a known pathogenic variant in PIK3CA, but no phase data or second-variant evidence was present in the reviewed workspace. Details ▾Hide ▴
Rule
Observed in cis or trans with a known pathogenic variant in the same gene.
Evidence considered
  • No cis/trans evidence assembled
Still missing
  • Phase information
  • Evidence of a second pathogenic variant in the same gene
Sources
vcep_db/PIK3CA/criteria.json:BP2output/case_summary.json
BP5 No alternate molecular explanation for the phenotype was documented in the assembled workspace, so BP5 was not assessed. Details ▾Hide ▴
Rule
Variant found in a case with an alternate molecular basis for disease.
Evidence considered
  • No alternate-cause evidence assembled
Still missing
  • Documented alternate molecular basis for disease
Sources
vcep_db/PIK3CA/criteria.json:BP5output/case_summary.json
Not applicable · 17· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThe Brain Malformations VCEP specifies PVS1 as not applicable for PIK3CA because the disease mechanism is gain-of-function rather than loss-of-function, so this frameshift is not evaluated with PVS1 in this framework. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
  • VCEP instruction: LOF/haploinsufficiency not clearly identified; disease mechanism is GOF
Sources
vcep_db/PIK3CA/criteria.json:PVS1output/final_classification_framework.json
PS1 N/APS1 is intended for the same amino acid change caused by a different nucleotide change. This variant is a frameshift event, not a single amino acid substitution, so PS1 was not applied. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Evidence considered
  • Protein consequence p.(Asn1068LysfsTer5) / p.(N1068Kfs*5)
Sources
vcep_db/PIK3CA/criteria.json:PS1output/prefetch.json:protein consequence
PM3 N/AThe Brain Malformations VCEP marks PM3 as not applicable because these disorders are evaluated as heterozygous, not recessive. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
  • VCEP instruction: not applicable since disease-causing variants are heterozygous
Sources
vcep_db/PIK3CA/criteria.json:PM3
PM4 N/AAlthough this is an indel-derived protein-length change, the Brain Malformations VCEP explicitly states PM4 is not used for these genes because in-frame indels are exceptionally rare and PM4 remains unsuitable in this gain-of-function framework. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
  • Variant consequence is frameshift
  • VCEP instruction marks PM4 not applicable
Sources
vcep_db/PIK3CA/criteria.json:PM4output/prefetch.json:protein consequence
PM5 N/APM5 is a novel missense-at-same-residue rule. This variant is a frameshift, so PM5 was not applied. Details ▾Hide ▴
Rule
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
Evidence considered
  • Protein consequence p.(Asn1068LysfsTer5) / p.(N1068Kfs*5)
Sources
vcep_db/PIK3CA/criteria.json:PM5output/prefetch.json:protein consequence
PM6 N/AThe Brain Malformations VCEP states that PM6 is addressed under PS2 and will not be used separately. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
  • VCEP instruction: this point is addressed according to PS2 and will not be used
Sources
vcep_db/PIK3CA/criteria.json:PM6
PP1 N/AThe Brain Malformations VCEP marks PP1 as not applicable because disease-causing variants in this setting are generally de novo, mosaic, or post-zygotic rather than segregating through multiplex families. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
  • VCEP instruction: not applicable since disease-causing variants are germline mosaic, de novo or mosaic
Sources
vcep_db/PIK3CA/criteria.json:PP1
PP2 N/AAlthough the PIK3CA gene-level missense constraint rule exists in this VCEP, PP2 is a missense criterion and this variant is a frameshift, so PP2 was not applied. Details ▾Hide ▴
Rule
Award PP2 if the missense z-score > 3.09 for applicable genes.
Evidence considered
  • Protein consequence p.(Asn1068LysfsTer5) / p.(N1068Kfs*5)
Sources
vcep_db/PIK3CA/criteria.json:PP2output/prefetch.json:protein consequence
PP3 N/AThe Brain Malformations VCEP explicitly marks PP3 as not applicable for these gain-of-function genes. The available SpliceAI result therefore was not used to activate PP3. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
  • SpliceAI max delta 0.03
  • VCEP instruction: PP3 not applicable for GOF variants
Sources
vcep_db/PIK3CA/criteria.json:PP3output/evidence.json:spliceai
PP4 N/AThe Brain Malformations VCEP states PP4 is not applicable because phenotype specificity is accounted for under PS4. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
  • VCEP instruction: accounted for under PS4
Sources
vcep_db/PIK3CA/criteria.json:PP4
PP5 N/AThe VCEP does not permit use of PP5. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
  • VCEP instruction: criterion not for use
Sources
vcep_db/PIK3CA/criteria.json:PP5
BS4 N/AThe Brain Malformations VCEP marks BS4 as not applicable in this context because relevant variants are typically de novo, mosaic, or post-zygotic rather than evaluated through non-segregation. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
  • VCEP instruction: not applicable as these are de novo, germline mosaic or post-zygotic mutations
Sources
vcep_db/PIK3CA/criteria.json:BS4
BP1 N/AThe Brain Malformations VCEP marks BP1 as not applicable because loss-of-function is not the disease mechanism. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
  • VCEP instruction: not applicable as LOF is not the disease mechanism
Sources
vcep_db/PIK3CA/criteria.json:BP1
BP3 N/AThe Brain Malformations VCEP marks BP3 as not applicable because these genes do not have relevant repetitive regions without known function for this rule. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
  • VCEP instruction: exon regions do not have repetitive regions without a known function
Sources
vcep_db/PIK3CA/criteria.json:BP3
BP4 N/AUnder this VCEP, BP4 is limited to synonymous, intronic non-canonical, or UTR variants when splicing tools predict no impact. This variant is a coding frameshift, so BP4 was not applied despite low SpliceAI scores. Details ▾Hide ▴
Rule
Not applicable except for synonymous, intronic non-canonical, or UTR variants.
Evidence considered
  • SpliceAI max delta 0.03
  • Protein consequence p.(Asn1068LysfsTer5) / p.(N1068Kfs*5)
Sources
vcep_db/PIK3CA/criteria.json:BP4output/evidence.json:spliceaioutput/prefetch.json:protein consequence
BP6 N/AThe VCEP does not permit use of BP6. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
  • VCEP instruction: criterion not for use
Sources
vcep_db/PIK3CA/criteria.json:BP6
BP7 N/ABP7 is limited to synonymous, intronic non-canonical, or UTR variants with low conservation/no splice impact. This variant is a coding frameshift, so BP7 was not applied. Details ▾Hide ▴
Rule
For synonymous, intronic positions (except canonical splice sites) and non-coding UTR variants, if the nucleotide is non-conserved award this point.
Evidence considered
  • Protein consequence p.(Asn1068LysfsTer5) / p.(N1068Kfs*5)
Sources
vcep_db/PIK3CA/criteria.json:BP7output/prefetch.json:protein consequence

Identifiers

Gene
PIK3CA
Transcript
NM_006218.4
Coding (HGVS c.)
NM_006218.4:c.3203dup
Protein (HGVS p.)
NP_006209.2:p.(Asn1068LysfsTer5)
GRCh38
chr3:179234358 G>GA
GRCh37
chr3:178952146 G>GA

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…
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/AThe Brain Malformations VCEP explicitly marks PP3 as not applicable for these gain-of-function genes. The available SpliceAI result therefore was not used to activate PP3. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
  • SpliceAI max delta 0.03
  • VCEP instruction: PP3 not applicable for GOF variants
Sources
vcep_db/PIK3CA/criteria.json:PP3output/evidence.json:spliceai
BP4 N/AUnder this VCEP, BP4 is limited to synonymous, intronic non-canonical, or UTR variants when splicing tools predict no impact. This variant is a coding frameshift, so BP4 was not applied despite low SpliceAI scores. Details ▾Hide ▴
Rule
Not applicable except for synonymous, intronic non-canonical, or UTR variants.
Evidence considered
  • SpliceAI max delta 0.03
  • Protein consequence p.(Asn1068LysfsTer5) / p.(N1068Kfs*5)
Sources
vcep_db/PIK3CA/criteria.json:BP4output/evidence.json:spliceaioutput/prefetch.json:protein consequence
BP7 N/ABP7 is limited to synonymous, intronic non-canonical, or UTR variants with low conservation/no splice impact. This variant is a coding frameshift, so BP7 was not applied. Details ▾Hide ▴
Rule
For synonymous, intronic positions (except canonical splice sites) and non-coding UTR variants, if the nucleotide is non-conserved award this point.
Evidence considered
  • Protein consequence p.(Asn1068LysfsTer5) / p.(N1068Kfs*5)
Sources
vcep_db/PIK3CA/criteria.json:BP7output/prefetch.json:protein consequence

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).

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
Cancer hotspots Captured Cancer Hotspots source record
OncoKB Captured OncoKB source record Open source ↗
ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

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 has been reported in ClinVar as Likely pathogenic (1 clinical laboratory).

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).

Functional

OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Gain-of-function.

Somatic

This variant has previously been reported in somatic cancers (COSMIC; COSV55878665, n = 29 times).