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.1 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.2 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 PS3.3 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.4
Final classification
Unclassified
PM1PM2
PIK3CA
c.3203dup
p.Asn1068LysfsTer5
This variant
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.
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.
Classification rationale
PM1PM2
Unclassified
PIK3CA c.3203dup
PM1 + PM2
→
Unclassified
1
output/evidence.json:cosmicoutput/evidence.json:clinvar
2
output/evidence.json:gnomad.GNOMAD_V2_1output/evidence.json:gnomad.GNOMAD_V4_1vcep_db/PIK3CA/criteria.json:PM2/BA1/BS1/BS2
3
output/prefetch.json:protein consequencevcep_db/PIK3CA/files/clingen_brainmalform_acmg_specifications_v1_1.pdf Table 4output/evidence.json:oncokboutput/literature_pass.json:PMID 29533785
4
output/evidence.json:spliceaivcep_db/PIK3CA/criteria.json:PP3/BP4/BP7
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.
Gene diagram
· NM_006218.4 · variants mapped to exon structure
PIK3CA
NM_006218.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 9 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
PM1
Supporting
review
Pathogenic
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.
Protein consequence p.(Asn1068LysfsTer5) / p.(N1068Kfs*5)BMVCEP Table 4 PIK3CA domain AA 797-1068
PM2
Supporting
review
Pathogenic
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.
Absent from gnomAD v2.1Absent from gnomAD v4.1
Assessed · not applied
· 3 not met · 6 not assessed
Pathogenic
PS2
The VCEP requires parental absence and/or tissue mosaic distribution data for PS2.
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.
PS4
The VCEP uses a phenotype-point system for PS4 and requires PM2 first.
Benign
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.
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.
BS2
BS2 requires at least 3 homozygotes in gnomAD or at least 3 well-phenotyped heterozygous family members.
BS3
No well-established benign functional study for this exact variant is documented in the workspace.
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.
BP5
No alternate molecular explanation for the phenotype was documented in the assembled workspace, so BP5 was not assessed.
N/A · 17
PVS1 · PS1 · PM3 · PM4 · PM5 · PM6 · PP1 · PP2 · PP3 · PP4 · PP5 · BS4 · BP1 · BP3 · BP4 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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.
COSMIC
Cancer hotspots
Somatic evidence
COSMIC
This variant has previously been reported in somatic cancers (COSMIC; COSV55878665, n = 29 times).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Sources & reference links