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PIK3CA
Final classification
VUS
PM2
PIK3CA
c.317G>C
p.Gly106Ala
missense · exon 2

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 encodes the p110α catalytic subunit of PI3K, a cancer driver whose aberrant activation fuels tumor growth via the AKT-mTOR pathway. A VUS for c.317G>C (p.Gly106Ala) means current evidence cannot establish whether this missense change alters PI3K signaling; it meets neither pathogenic nor benign criteria and should not be assumed to drive disease.

Transcript
NM_006218.4
HGVS · transcript:coding
NM_006218.4:c.317G>C
GRCh38
chr3:179199142 G>C
GRCh37
chr3:178916930 G>C
Basis VUS: the only applied criterion was PM2 (Supporting), absence from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, and a single supporting criterion alone reaches no pathogenic or benign combination threshold.
VUS: the only applied criterion was PM2 (Supporting), absence from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, and a single supporting criterion alone reaches no pathogenic or benign combination threshold.
Classification rationale
PM2 VUS
PIK3CA c.317G>C missense · exon 2

PM2 (Supporting): variant absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, with no observed control carriers. Overall classification: VUS — the single supporting PM2 criterion does not reach any pathogenic or benign combination threshold under ACMG/AMP 2015 rules.

PM2 VUS
Gene diagram · NM_006218.4 · variants mapped to exon structure
PIK3CA NM_006218.4
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 13 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
PM2 supporting Pathogenic
Met (Supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, with no observed control carriers.
The governing Brain Malformations VCEP specifies PM2 at Supporting strength when the variant is absent/rare in an ethnically matched cohort population sample, allowing a maximum of one person.Direct variant queries report NM_006218.4:c.317G>C as absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0; the available control datasets therefore show zero observed carriers, within the VCEP maximum of one person.
Assessed · not applied · 4 not met · 9 not assessed
Pathogenic
PS1 Not assessed: no ClinVar record, literature PMID, or prior pathogenic report of the same amino acid change was available.
PS2 Not assessed: no proband genotype, parental testing, or confirmed de novo evidence was available.
PS3 Not assessed: no variant-specific functional assay or animal-model evidence was available.
PS4 Not assessed: no affected-individual phenotype data or case-control enrichment evidence was available.
PM1 Not met: Gly106 lies outside the VCEP kinase-domain intervals (residues 322-483 and 797-1068), and the Cancer Hotspots hit does not satisfy this domain rule.
PM5 Not assessed: no different missense change at residue Gly106 previously determined pathogenic was identified.
PP2 Not assessed: no PIK3CA missense-constraint z-score was available to adjudicate the >3.09 threshold.
Benign
BA1 Not met: variant is absent from gnomAD, below the >0.0926% allele-frequency BA1 threshold.
BS1 Not met: variant is absent from gnomAD, below the >0.0185% allele-frequency BS1 threshold.
BS2 Not met: BS2 requires at least 3 homozygotes or 3 heterozygous family observations; none were present.
BS3 Not assessed: no functional assay evidence demonstrating no damaging effect on protein function was available.
BP2 Not assessed: no phase results or co-occurring known pathogenic PIK3CA variant were available.
BP5 Not assessed: no alternate molecular diagnosis explaining the phenotype was documented.
N/A · 14 PVS1 · PM3 · PM4 · PM6 · PP1 · PP3 · PP4 · PP5 · BS4 · BP1 · BP3 · BP4 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
ClinVar screenshot
ClinVar
This variant is absent from ClinVar.
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05). REVEL score = 0.658. BayesDel score = 0.229847.
Functional / OncoKB screenshot
Functional Likely Oncogenic
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PIK3CA, the catalytic subunit of PI3-kinase, is frequently mutated in a diverse range of cancers including breast, endometrial and cervical cancers.
OncoKB ↗
COSMIC screenshot
COSMIC
Cancer hotspots screenshot
Cancer hotspots
Somatic evidence Hotspot
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55888676, n = 2 times).
Hotspots
This variant lies in a statistically significant hotspot.
Sources & reference links
9Sources
CSpec VCEP
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Cancer hotspots