PIK3CA encodes the p110α catalytic subunit of phosphoinositide 3-kinase (PI3K), an enzyme that converts the membrane lipid PIP2 into PIP3, thereby activating signaling cascades such as the AKT-mTOR pathway that promote cell survival, proliferation, growth, and motility. It is among the most commonly mutated genes in cancer, and aberrant activation of PI3K signaling is a driving event in tumor development, with the gene implicated in cancers including cervical cancer. Because this pathway is central to tumor growth, it is a major target of cancer therapies, although drug-induced pathway activation can also contribute to treatment resistance.
This variant
PIK3CA drives tumor growth and brain malformations through gain-of-function activation of PI3K-AKT-mTOR signaling, a mechanism central to its role in cancers such as cervical cancer. This C-terminal frameshift, predicted to produce p.(Gln1064ThrfsTer9), truncates the protein rather than creating the activating change typical of PIK3CA disease, and its VUS classification reflects insufficient evidence to establish or exclude a disease-driving effect.
Transcript
NM_006218.4
HGVS · transcript:coding
NM_006218.4:c.3189dup
GRCh38
chr3:179234343 T>TA
GRCh37
chr3:178952131 T>TA
The PIK3CA Brain Malformations VCEP defines no combination framework, so generic ACMG/AMP 2015 rules applied; the sole met criterion (PM2, Supporting) satisfies no Pathogenic or Likely Pathogenic combination, yielding VUS.
Classification rationale
PM2VUS
PIK3CA c.3189dupframeshift · exon 21
PM2 (Supporting): the exact variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Overall classification: VUS - PM2 at Supporting strength is the only met criterion and satisfies no ACMG/AMP 2015 Pathogenic or Likely Pathogenic combination.
PM2→VUS
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
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—click a row to locate it on the plot · use the link column to open its page
Protein
Location
Classification
Link
Applied criteria · 1 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 · 1
Strength Supporting Moderate Strong Very strong
✓
PM2supportingreviewPathogenic
Met (Supporting): the exact variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0. Flagged for human review: indel population calls may be unreliable and coverage/quality metrics were not available.
The applicable ClinGen Brain Malformations VCEP specification assigns PM2 at Supporting strength for an absent/rare variant in an ethnically matched cohort population sample, with at least one qualifying sample sufficient.The exact variant NM_006218.4:c.3189dup was reported absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0.The specification's generic PM2 caveat states that population data for indels may be poorly called by next-generation sequencing; no dataset-specific coverage or quality metrics were supplied in the case evidence bundle.
Assessed · not applied
· 3 not met · 6 not assessed
Pathogenic
PS2Not assessed: no proband phenotype, parental genotypes, or de novo testing results were available, so de novo occurrence cannot be evaluated.
PS3Not assessed: no validated variant-specific functional assay or animal-model evidence was available.
PS4Not assessed: no affected cerebral-malformation cases, case-control data, or phenotype-point evidence for this exact variant were available.
Benign
BA1Not met: the variant is absent (frequency 0) from all gnomAD sources, far below the VCEP BA1 threshold of >0.0926%.
BS1Not met: the variant is absent from gnomAD, far below the VCEP BS1 threshold of >0.0185%.
BS2Not met: BS2 requires at least 3 gnomAD homozygotes or 3 heterozygous well-phenotyped relatives; the variant is absent from gnomAD with no such family observations.
BS3Not assessed: no functional assay or animal-model evidence demonstrating absence of a damaging effect was available.
BP2Not assessed: no genotype data, second PIK3CA variant, or phase information was available to assess cis/trans status with a pathogenic allele.
BP5Not assessed: no individual carrying this variant with an alternate molecular diagnosis was reported.
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55934843, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
