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NM_006218.4:c.3G>A
p.Met1? · PIK3CA
0%
complete
Final classification
VUS
PM2
PIK3CA
c.3G>A
p.Met1?
initiation_loss · 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, whose activation of AKT-mTOR signaling promotes cell survival, proliferation, growth, and motility and contributes to tumor development.

Transcript
NM_006218.4
HGVS · transcript:coding
NM_006218.4:c.3G>A
GRCh38
chr3:179198828 G>A
GRCh37
chr3:178916616 G>A
VUS: PM2 (supporting) is the only met criterion and does not satisfy a generic ACMG/AMP pathogenic, benign, or likely benign combination rule.
Classification rationale
PM2 VUS
PIK3CA c.3G>A initiation_loss · exon 2

VUS: PM2 supporting is met because the variant has 0 of 1,513,740 alleles and 0 homozygotes in gnomAD v4.1.

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
PIK3CA NM_006218.4
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 11 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 at supporting: the variant has 0/1,513,740 alleles and 0 homozygotes in gnomAD v4.1, within the VCEP one-person maximum.
The ClinGen Brain Malformations VCEP specifies PM2 at supporting strength for an allele absent or rare in an ethnically matched population sample, with a one-person maximum.gnomAD v2.1 reports the variant absent.gnomAD v4.1 reports exome AC 0 of 1,361,480, total AC 0 of 1,513,740, AF 0, and zero homozygotes, including zero in the highest-observed African/African American population.
Assessed · not applied · 5 not met · 6 not assessed
Pathogenic
PS2 Not assessed: no proband, parental testing, maternity/paternity confirmation, or tissue allele-fraction data are available to meet the VCEP PS2 criteria.
PS3 Not assessed: available functional papers do not test c.3G>A (p.M1?), so no variant-specific damaging assay result meets the VCEP PS3 requirements.
PS4 Not assessed: the variant is absent from gnomAD, but no verified affected-individual phenotype observation was available to assign Table 2A PS4 points.
PP5 Not met: ClinVar has no exact-variant expert-panel pathogenic or likely pathogenic classification for NM_006218.4:c.3G>A.
Benign
BA1 Not met: gnomAD v4.1 allele frequency is 0/1,513,740 (0%), below the VCEP BA1 threshold of >0.0926%.
BS1 Not met: gnomAD v4.1 allele frequency is 0/1,513,740 (0%), below the VCEP BS1 threshold of >0.0185%.
BS2 Not met: gnomAD v4.1 reports 0 homozygotes, below the VCEP requirement of at least 3 homozygotes or 3 qualifying family observations.
BS3 Not assessed: no fetched functional paper tests c.3G>A (p.M1?) and reports a validated normal-function result required for BS3.
BP2 Not assessed: no documented cis/trans PIK3CA pathogenic-variant pair or phase result is available for NM_006218.4:c.3G>A.
BP5 Not assessed: no case was documented in which this exact variant co-occurred with a confirmed alternate molecular basis in another gene.
BP6 Not met: ClinVar has no exact-variant expert-panel benign or likely benign classification for NM_006218.4:c.3G>A.
N/A · 16 PVS1 · PS1 · PM1 · PM3 · PM4 · PM5 · PM6 · PP1 · PP2 · PP3 · PP4 · BS4 · BP1 · BP3 · BP4 · BP7
Research & evidence
Population frequency
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1513740 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/71510 alleles, homozygotes = 0).
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 / 1,513,740
0 hom
Not observed in any ancestry group.
+ 10 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))
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 = 0.01). REVEL score = 0.65. BayesDel score = 0.66.
Functional / OncoKB screenshot
Functional Inconclusive
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Inconclusive; curated oncogenicity label: Inconclusive.
OncoKB ↗
COSMIC screenshot
COSMIC
Cancer hotspots screenshot
Cancer hotspots
Somatic evidence Hotspot
COSMIC
This variant lies in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
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
Triaged references · 2 PMIDs not cited in assessment
29533785 ↗ Systematic Functional Annotation of Somatic Mutations in Cancer. ONCOKB
31996845 ↗ PIK3CA variants selectively initiate brain hyperactivity during gliomagenesis. ONCOKB