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
The PIK3CA E542V variant has been functionally characterized as oncogenic. It is located in the helical domain of the protein and confers a gain of function. Experimental evidence demonstrates that this mutation leads to increased downstream pathway activation, including enhanced phosphorylation of Akt and Mek1/2, and supports growth-factor independent cell survival. It is also transforming in cell culture models.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | -85 bp |
| Donor Loss (DL) | 0.0 | 39 bp |
| Acceptor Gain (AG) | 0.01 | 14 bp |
| Donor Gain (DG) | 0.0 | 467 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to standard ACMG guidelines, the rule for PVS1 is: null variants (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single‐ or multi‐exon deletion) in a gene where loss of function is a known mechanism of disease. The evidence for this variant shows: NM_006218.4:c.1625A>T is a missense change, not predicted to cause loss of function. Therefore, this criterion is not applied.
PS1 (Not Applied)
According to standard ACMG 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: E542V is a distinct amino acid change from the known pathogenic E542K. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 is: Strong if de novo with confirmed maternity/paternity and tissue evidence; Moderate if partially fulfilled. The evidence for this variant shows: no de novo or parental testing data available. Therefore, this criterion is not applied.
PS3 (Strong)
According to VCEP guidelines, the rule for PS3 is: Award PS3 if the functional assay meets the acceptability criteria delimited in (PMID: 31892348) with specifications added by the BMVCEP. The evidence for this variant shows: well‐established in vitro studies demonstrate gain‐of‐function in the helical domain with increased Akt/Mek1/2 phosphorylation and transforming activity. Therefore, this criterion is applied at Strong strength because the functional assays meet VCEP quality metrics supporting a damaging effect.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: points‐based case evidence only if variant meets PM2, with thresholds for Supporting, Moderate, Strong, Very Strong. The evidence for this variant shows: no published case series or phenotype scoring available. Therefore, this criterion is not applied.
PM1 (Supporting)
According to VCEP guidelines, the rule for PM1 is: Residues affecting critical functional domains provided in Table 4 for each gene (Supporting strength). The evidence for this variant shows: E542 is in the well‐established helical domain mutational hotspot of PIK3CA. Therefore, this criterion is applied at Supporting strength because it lies in a critical functional domain without benign variation.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 is: Absent/rare from controls in an ethnically‐matched cohort population sample (Supporting strength). The evidence for this variant shows: not found in gnomAD (MAF 0%). Therefore, this criterion is applied at Supporting strength because it is absent from population controls.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: for recessive disorders, detection in trans with a pathogenic variant. The evidence for this variant shows: PIK3CA E542V is not studied in a recessive context and no trans data. 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 indels or stop‐loss. The evidence for this variant shows: E542V is a missense change without protein length alteration. Therefore, this criterion is not applied.
PM5 (Moderate)
According to standard ACMG guidelines, the rule for PM5 is: novel missense change at an amino acid residue where a different pathogenic missense change has been observed (Moderate strength). The evidence for this variant shows: E542K is a well‐established pathogenic variant at the same residue. Therefore, this criterion is applied at Moderate strength because this is a novel change at a codon with known pathogenic variation.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: assumed de novo without confirmation. The evidence for this variant shows: no de novo data. 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. The evidence for this variant shows: no family segregation data. Therefore, this criterion is not applied.
PP2 (Supporting)
According to VCEP guidelines, the rule for PP2 is: missense constraint computed in ExAC/gnomAD with z‐score >3.09 applicable to PIK3CA (Supporting strength). The evidence for this variant shows: PIK3CA exhibits high missense constraint (z‐score >3.09). Therefore, this criterion is applied at Supporting strength because the gene is constrained for missense variation.
PP3 (Not Applied)
According to standard ACMG guidelines, the rule for PP3 is: multiple lines of computational evidence support a deleterious effect. The evidence for this variant shows: mixed in silico predictions (some tools benign, some pathogenic). 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. The evidence for this variant shows: no clinical phenotype or family history provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: reputable source reports the variant as pathogenic without available evidence. The evidence for this variant shows: not present in ClinVar or other databases. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: allele frequency >0.0926% in general population (Stand‐alone). The evidence for this variant shows: MAF 0% in gnomAD. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: allele frequency >0.0185% in population (Strong). The evidence for this variant shows: MAF 0% in gnomAD. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: ≥3 homozygotes or well‐phenotyped heterozygotes in population (Strong). The evidence for this variant shows: no homozygotes or reported heterozygotes. 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 (Strong/Supporting). The evidence for this variant shows: functional studies show a damaging gain‐of‐function effect. 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 of a family. The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: missense variant in gene where only truncating variants cause disease. The evidence for this variant shows: PIK3CA is an oncogene driven by missense gain‐of‐function. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: observed in trans with a pathogenic variant for a recessive disorder. The evidence for this variant shows: no trans data or recessive context. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: in‐frame indels in repetitive regions without functional impact. The evidence for this variant shows: missense, not an indel. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: applicable only to synonymous, intronic (except canonical splice sites), or UTR variants if splicing tools predict no impact. The evidence for this variant shows: missense change. 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 alternate molecular basis for disease. The evidence for this variant shows: no such data. 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. The evidence for this variant shows: no database entries. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: synonymous or intronic variants with low conservation. The evidence for this variant shows: missense variant. Therefore, this criterion is not applied.