Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_006218.2 | Alternative | 3724 nt | 158–3364 |
| NM_006218.3 | Alternative | 9104 nt | 158–3364 |
| NM_006218.4 | MANE Select | 9259 nt | 324–3530 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open""
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | 21 bp |
| Donor Loss (DL) | 0.03 | -71 bp |
| Acceptor Gain (AG) | 0.0 | -65 bp |
| Donor Gain (DG) | 0.0 | -259 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to standard ACMG guidelines, the rule for PVS1 is: "Null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where LOF is a known mechanism of disease." The evidence for this variant shows it is a missense change (L94P), not a null variant. Therefore, this criterion is not applied.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change." The evidence for this variant shows no previously established pathogenic L94P or other L94* change. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2_Strong is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." No de novo or parental testing data are available for this variant. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to VCEP guidelines, functional evidence (PS3) requires validated assays demonstrating a damaging effect. No functional studies have been performed for L94P. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: "Case-control or phenotypic observations points for absent/rare variants meeting PM2." No case or segregation data are reported. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines, the rule for PM1_Supporting is: "Residues affecting critical functional domains provided in Table 4 for each gene." Position 94 is not in a recognized PIK3CA hotspot or critical functional domain defined by the VCEP. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2_Supporting is: "Absent/rare from controls in an ethnically-matched cohort population sample (≥1)." The evidence for this variant shows it is absent from gnomAD and other population databases (MAF = 0%). Therefore, this criterion is applied at Supporting strength.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: "For recessive disorders, detected in trans with a pathogenic variant." No evidence of recessive inheritance or trans observations is available. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions in a non-repeat region." The variant is a missense substitution and does not change protein length. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different missense change is pathogenic." No other pathogenic variant at residue L94 has been reported. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, without confirmation of paternity and maternity." No parental or de novo data are available. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines, the rule for PP1 is: "Cosegregation with disease in multiple affected family members." No segregation data are available. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to VCEP guidelines, the rule for PP2_Supporting is: "Missense constraint computed in ExAC/gnomAD; z-score > 3.09." No z-score data are provided for PIK3CA at this position. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to standard ACMG guidelines, the rule for PP3 is: "Multiple computational evidence supporting a deleterious effect on the gene or gene product." In silico predictions are mixed (some tools deleterious, others benign; SpliceAI shows no splicing impact). Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology." No detailed phenotypic data are provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic without available evidence." The variant is not in ClinVar or other reputable databases. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: "Allele frequency (> 0.0926%)." The variant is absent from population databases. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: "Allele frequency (> 0.0185%)." The variant is absent from population databases. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: "Observed in ≥ 3 healthy individuals or homozygotes in population databases." The variant is not observed in any healthy cohorts. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: "Well-established functional studies show no damaging effect." No such functional studies exist. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected members." No segregation data are provided. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene for which only truncating variants cause disease." PIK3CA disease mechanism is gain-of-function, not LOF. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: "Observed in cis with a pathogenic variant in the same gene." No such observations are reported. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in repetitive regions without known function." The variant is a missense substitution. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: "Not applicable for any variant type except for synonymous, intronic, or UTR variants." This is a missense variant. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternative molecular basis for disease." No such cases are reported. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign without evidence." No reputable source classification exists. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: "Synonymous or intronic variant with low conservation." This is a missense variant. Therefore, this criterion is not applied.