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
PIK3CA
Final classification
Unclassified
PIK3CA c.3203dup · p.Asn1068LysfsTer5
PIK3CA
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
Gene diagram
· NM_006218.4 · variants mapped to exon structure
PIK3CA
NM_006218.4
Fetching transcript structure from UCSC…
Applied criteria · 2 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
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