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 C407F variant has not been functionally characterized, and its effect on protein function is currently unknown.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | -74 bp |
| Donor Loss (DL) | 0.0 | 31 bp |
| Acceptor Gain (AG) | 0.01 | 12 bp |
| Donor Gain (DG) | 0.0 | 20 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, start codon, splicing +1/2) in a gene where LOF is a known mechanism of disease.' The evidence for this variant shows: it is a missense change (C407F), not a null variant. Therefore, this criterion is not applied.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: '**Strong Strength**: Strong No change.' The evidence for this variant shows: no previously established pathogenic variant results in the same amino acid change at position 407. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 is: 'Strong: Award PS2_Strong if Criteria 1 AND Criteria 2 are fulfilled; Moderate: Award PS2_Moderate if Criteria 1 is fulfilled or if parents are not available but Criteria 2 is fulfilled.' The evidence for this variant shows: no data on de novo occurrence or mosaicism. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to VCEP guidelines, the rule for PS3 is: 'Strong, Moderate, or Supporting depending on validated functional assay quality metrics.' The evidence for this variant shows: no functional studies have been performed. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: 'Points assigned based on phenotypic case data to determine strength; applicable only if variant meets PM2.' The evidence for this variant shows: no reported cases in the literature or patient cohorts. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines, the rule for PM1 is: 'Supporting for residues affecting critical functional domains provided in Table 4 for each gene.' The evidence for this variant shows: position 407 is not within a VCEP-defined hotspot or critical domain for PIK3CA. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 is: 'Supporting 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: 'Detected in trans with a pathogenic variant for a recessive disorder.' The evidence for this variant shows: PIK3CA disorders are not recessive and no trans observations. 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 variants.' The evidence for this variant shows: it is a missense substitution without length change. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5 is: 'Moderate Strength: No change.' The evidence for this variant shows: no other missense change at codon 407 has been established as pathogenic. Therefore, this criterion is not applied.
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: 'Co-segregation with disease in multiple affected family members.' The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
PP2 (Supporting)
According to VCEP guidelines, the rule for PP2 is: 'Supporting Strength: Missense constraint computed in ExAC/gnomAD (z-score >3.09) applicable to PIK3CA.' The evidence for this variant shows: PIK3CA is missense-constrained (z-score >3.09) and this is a missense change. Therefore, this criterion is applied at Supporting strength.
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: in silico tools yield mixed predictions with no consensus. 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 highly specific for gene.' The evidence for this variant shows: no phenotype data 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.' The evidence for this variant shows: not found in ClinVar or other databases. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: 'Stand Alone strength for allele frequency >0.0926%.' The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: 'Strong strength for allele frequency >0.0185%.' The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: 'Strong strength if ≥3 homozygotes or heterozygotes in well-phenotyped individuals.' The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: 'Strong or Supporting for well-validated functional assays showing no damaging effect.' The evidence for this variant shows: no functional assays performed. 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.' 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 loss-of-function causes disease.' The evidence for this variant shows: PIK3CA gain-of-function missense variants cause disease. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: 'Observed in cis or trans with a pathogenic variant in the same gene.' The evidence for this variant shows: no cis/trans observations. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: 'In-frame indels in repetitive region without known function.' The evidence for this variant shows: it is a missense variant, not an indel. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: 'Only for synonymous, intronic, or UTR variants if two of three splicing tools predict no impact.' The evidence for this variant shows: it is a 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.' The evidence for this variant shows: no such reports. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: 'For synonymous, intronic, or UTR variants with non-conserved nucleotide.' The evidence for this variant shows: it is a missense change. Therefore, this criterion is not applied.