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) | 0.01 | 9 bp |
| Donor Loss (DL) | 0.01 | -44 bp |
| Acceptor Gain (AG) | 0.0 | -139 bp |
| Donor Gain (DG) | 0.0 | 34 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 exon or multi-exon deletion) in a gene where loss-of-function is a known mechanism of disease." The evidence for this variant shows: it is a missense change (L719I), 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: there is no known pathogenic L719I or equivalent amino acid change reported. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history, or high-confidence somatic de novo criteria." The evidence for this variant shows: no de novo or somatic heterogeneity data are available. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to VCEP guidelines, the rule for PS3 is: "Well-validated functional studies showing a damaging effect on the gene or gene product." The evidence for this variant shows: no functional assays or animal models have been performed. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: "Increased prevalence in affected individuals compared to controls, scored by phenotype points, applicable only if PM2 is met." The evidence for this variant shows: no case-level phenotype data or counts are available. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines, the rule for PM1 is: "Supporting evidence for residues affecting critical functional domains (Table 4)." The evidence for this variant shows: L719 is not a known hotspot or critical residue listed in PIK3CA domain tables. 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." 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." The evidence for this variant shows: PIK3CA-related diseases are not recessive and no trans data exist. 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 evidence for this variant shows: it is a missense substitution, not an indel. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5 is: "Moderate: Novel missense change at an amino acid residue where a different pathogenic missense change has been seen." The evidence for this variant shows: no other pathogenic variant at residue 719 is reported. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity." The evidence for this variant shows: no de novo data are available. 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 family segregation data are available. Therefore, this criterion is not applied.
PP2 (Supporting)
According to VCEP guidelines, the rule for PP2 is: "Supporting: Missense constraint computed in ExAC/gnomAD with z-score > 3.09." The evidence for this variant shows: PIK3CA has a missense z-score above 3.09, indicating constraint. Therefore, this criterion is applied at Supporting strength.
PP3 (Not Applied)
According to standard ACMG guidelines, the rule for PP3 is: "Multiple computational lines of evidence support a deleterious effect." The evidence for this variant shows: in silico predictions are mixed (some benign, some deleterious), and SpliceAI predicts 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." The evidence for this variant shows: no clinical phenotype 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." The evidence for this variant shows: it is not present in ClinVar or other expert-curated pathogenic databases. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: "Stand Alone: 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: 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: ≥3 homozygotes or well‐phenotyped heterozygotes in controls." 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: Well-validated functional studies show no damaging effect." The evidence for this variant shows: no 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 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 a gene where only truncating variants cause disease." The evidence for this variant shows: PIK3CA disease mechanism involves gain-of-function missense variants. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to VCEP guidelines, the rule for BP2 is: "Supporting: Observed in cis or trans with a known pathogenic variant." The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "In-frame indel in a repetitive region without a known function." The evidence for this variant shows: it is a missense substitution, not an indel. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: "Supporting for synonymous or non-coding variants when two of three splicing tools predict no impact." The evidence for this variant shows: it is a missense variant, so BP4 is not applicable per VCEP. 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: it is not present in benign reference databases. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: "Supporting for synonymous or intronic variants with low conservation." The evidence for this variant shows: it is a missense variant. Therefore, this criterion is not applied.