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"This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The PIK3CA I910V variant has been functionally characterized with conflicting evidence. In MCF10A cells, the variant leads to increased proliferation in the absence of growth factors, suggesting a potential gain-of-function effect. However, this effect was not observed in Ba/F3 cells, and the variant has not been biochemically characterized, leaving its precise impact on PIK3CA protein function unclear.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.01 | 160 bp |
| Donor Loss (DL) | 0.0 | 59 bp |
| Acceptor Gain (AG) | 0.0 | -8 bp |
| Donor Gain (DG) | 0.02 | 38 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 loss of function is a known mechanism of disease." The evidence for this variant shows: c.2728A>G is a missense change (I910V), not a null variant. 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: there is no known pathogenic variant resulting in I910V. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." The evidence for this variant shows: no de novo segregation or family data are available. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to VCEP guidelines, the rule for PS3 is: "Follow recommendations set forth by the SVI with specifications for quality metrics and minimum validation controls required. Functional assays must meet acceptability criteria to provide strong evidence of pathogenicity." The evidence for this variant shows: conflicting functional results (increased proliferation in MCF10A cells but no effect in Ba/F3 cells) and no biochemical characterization. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 is: "The prevalence of the variant in affected individuals is significantly increased compared with controls." The evidence for this variant shows: no case–control or phenotype data are available. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines, the rule for PM1 is: "Supporting evidence if residue affects critical functional domains provided in Table 4 for each gene." The evidence for this variant shows: I910 is not located in a defined hotspot or critical functional 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: MAF=0% in gnomAD and other population databases. 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: no data on trans configuration with another pathogenic variant. 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 or stop-loss variants." The evidence for this variant shows: I910V is a missense substitution without change in 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 pathogenic missense change has been seen." The evidence for this variant shows: no other pathogenic missense changes reported at codon 910. 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 family 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 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 was utilized. Award PP2 if the z-score > 3.09 (applicable to MTOR, PIK3CA and AKT3)." The evidence for this variant shows: PIK3CA has a missense z-score > 3.09 in gnomAD. Therefore, this criterion is applied at Supporting strength.
PP3 (Not Applied)
According to VCEP guidelines, BP4/PP3 splicing rules apply only to synonymous or intronic variants; computational evidence for missense is not specified. The evidence for this variant shows: in silico tools predict a benign effect, but VCEP does not support PP3 for missense. 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 phenotype/family history 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: ClinVar reports Uncertain Significance. 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: MAF=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: MAF=0%. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: "Strong – ≥3 homozygotes in gnomAD or ≥3 heterozygotes in well-phenotyped family members." The evidence for this variant shows: no homozygotes or phenotyped heterozygotes observed. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: "Functional studies show no damaging effect on protein function or splicing." The evidence for this variant shows: functional data are conflicting and do not meet validation criteria. 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 available. 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 primarily truncating variants cause disease." The evidence for this variant shows: PIK3CA disease mechanism is gain-of-function, not loss-of-function, but BP1 is not applicable. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: "Observed in cis/trans with a pathogenic variant in the same gene." The evidence for this variant shows: no data on cis/trans observations. 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 a known function." The evidence for this variant shows: this is a missense variant. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: "Supporting – Applicable only to synonymous, intronic (non-canonical) or UTR variants when two of three splicing tools predict no impact." The evidence for this variant shows: I910V is missense; 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 case 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: ClinVar reports VUS only. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no predicted splice impact and nucleotide non-conservation." The evidence for this variant shows: it is missense, not synonymous. Therefore, this criterion is not applied.