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NM_006218.4:c.1634A>T
p.Glu545Val · PIK3CA
0%
complete
Final classification
VUS
PS4PM2
PIK3CA
c.1634A>T
p.Glu545Val
missense · exon 10

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, and altered PI3K–AKT-mTOR signaling can promote tumor growth and contribute to cancers including cervical cancer.

Transcript
NM_006218.4
HGVS · transcript:coding
NM_006218.4:c.1634A>T
GRCh38
chr3:179218304 A>T
GRCh37
chr3:178936092 A>T
VUS: PS4 (supporting) plus PM2 (supporting) provides two supporting criteria, insufficient for a pathogenic, likely pathogenic, likely benign, or benign ACMG/AMP classification.
Classification rationale
PS4PM2 VUS
PIK3CA c.1634A>T missense · exon 10

PS4 supporting: four reported COSMIC occurrences yield 1.00 VCEP points, within the supporting range. PM2 supporting: the variant is absent from the reported gnomAD datasets.

PS4 + 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 · 2 applied · 12 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
PS4 supporting review Pathogenic
Met at Supporting: four reported COSMIC occurrences yield 4 × 0.25 = 1.00 points, within the VCEP PS4 Supporting range of 0.5–1.25 points.
The governing VCEP Table 2A assigns 0.25 points for presence of the variant in a tumor sample and states that each separate primary counts as an occurrence, with normal tissue excluded and a maximum of nine tumor samples.The governing VCEP Table 2B defines PS4_Supporting as 0.5–1.25 points.The variant is reported absent from gnomAD v2.1 and gnomAD v4.1, satisfying the VCEP requirement that PS4 phenotype points require PM2.
PM2 supporting Pathogenic
Met, supporting: the variant is absent from gnomAD v2.1, v4.1, and non-cancer subsets, satisfying the VCEP one-person-maximum PM2 rule.
The governing ClinGen Brain Malformations VCEP defines PM2_Supporting as absent/rare in an ethnically matched cohort population sample with one person maximum.The case evidence reports this variant absent from gnomAD v2.1 and gnomAD v4.1.The case evidence also reports absence from gnomAD v2.1 non-cancer and gnomAD v3.1 non-cancer subsets.
Assessed · not applied · 4 not met · 8 not assessed
Pathogenic
PS1 Not assessed: no previously established pathogenic variant producing the same PIK3CA p.Glu545Val amino-acid change was identified in the reviewed sources.
PS2 Not assessed: no documented proband allele fraction, parental absence with confirmed maternity and paternity, or affected-versus-other-tissue comparison is available.
PS3 Not assessed: no reviewed functional assay directly tested PIK3CA p.Glu545Val, so variant-specific PS3 cannot be assigned.
PM1 Not met: PIK3CA residue 545 lies outside all approved PM1 domains, whose highest relevant interval ends at amino acid 483.
PM5 Not assessed: the collected PM5 search found 0 same-residue comparators, but candidate harvesting ended with an HTTP 429 retrieval failure.
PP2 Not assessed: the VCEP requires a PIK3CA missense-constraint z-score >3.09, but no applicable z-score is provided.
Benign
BA1 Not met: the variant is absent from gnomAD v2.1, v4.1, and non-cancer subsets, below the VCEP BA1 threshold of >0.0926%.
BS1 Not met: the variant is absent from all reported gnomAD datasets, below the VCEP BS1 allele-frequency threshold of >0.0185%.
BS2 Not met: no homozygous gnomAD observations or qualifying healthy-family observations are reported, versus the VCEP requirement of at least 3.
BS3 Not assessed: no reviewed assay directly showed preserved function for PIK3CA p.Glu545Val, so BS3 cannot be assigned.
BP2 Not assessed: no documented cis or trans observation with a known pathogenic PIK3CA variant is available for NM_006218.4:c.1634A>T.
BP5 Not assessed: no documented case shows this exact variant with an alternate molecular diagnosis in a different gene.
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
Not available in 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 = 0.01). REVEL score = 0.73. BayesDel score = 0.276467.
Functional / OncoKB screenshot
Functional Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
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; COSV55892885, n = 4 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
Triaged references · 2 PMIDs not cited in assessment
19349352 ↗ Frequent activating mutations of PIK3CA in ovarian clear cell carcinoma. ONCOKB
24504419 ↗ Antitumor activity and induction of TP53-dependent apoptosis toward ovarian clea ONCOKB