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 V101_I102delinsF variant has been functionally characterized as likely oncogenic, indicating a damaging effect.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.01 | 1 bp |
| Donor Loss (DL) | 0.01 | -1 bp |
| Acceptor Gain (AG) | 0.01 | 16 bp |
| Donor Gain (DG) | 0.07 | -91 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: it is an in‐frame deletion‐insertion, not predicted to cause loss of function. Therefore, this criterion is not applied.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: "Strong: same amino acid change as previously established pathogenic variant by a different nucleotide change." The evidence for this variant shows: it results in a novel in‐frame delins (V101_I102delinsF), not identical to any known pathogenic amino acid substitution. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2_Strong is: "Award PS2_Strong if Criteria 1 AND Criteria 2 are fulfilled: de novo in germline with confirmed maternity/paternity and mosaic distribution across tissues." The evidence for this variant shows: no de novo or parental testing data are 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 functional studies have characterized PIK3CA V101_I102delinsF as likely oncogenic, meeting the required quality metrics. Therefore, this criterion is applied at Strong strength because a validated functional assay demonstrates a damaging effect.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: "Points assigned for phenotype according to Table 2A; strength determined by total points (e.g., ≥16 points for PS4_VeryStrong)." The evidence for this variant shows: no case‐level phenotype data or point totals are available. 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." The evidence for this variant shows: V101_I102 is not located in a known critical PIK3CA functional domain or hotspot. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 is: "Absent/rare from controls in an ethnically-matched cohort population sample (≥1)." The evidence for this variant shows: it is not found in gnomAD, 1000G, ESP or ExAC. Therefore, this criterion is applied at Supporting strength because the variant is absent from population controls.
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‐related disease is not recessive and no trans data are available. Therefore, this criterion is not applied.
PM4 (Moderate)
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 causes an in‐frame deletion‐insertion replacing two amino acids with one phenylalanine in a non‐repetitive region. Therefore, this criterion is applied at Moderate strength because it results in a protein length change outside of a repetitive context.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5 is: "Moderate: novel missense change at a codon where a different pathogenic missense change has been observed." The evidence for this variant shows: it is an in‐frame indel, not a novel missense. 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/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: "Cosegregation with disease in multiple affected family members." The evidence for this variant shows: no family segregation data are provided. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to VCEP guidelines, the rule for PP2 is: "Missense constraint (ExAC/gnomAD z-score >3.09) for MTOR, PIK3CA, AKT3 applies to missense variants." The evidence for this variant shows: it is an in‐frame indel, not a missense. Therefore, this criterion is not applied.
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 (SpliceAI ≤0.07, conservation) predict no 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 single gene disorder." The evidence for this variant shows: no 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 (e.g., ClinVar) reports the variant as pathogenic." The evidence for this variant shows: it is not found in ClinVar. 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." 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: "Allele frequency >0.0185% in general population." 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: "≥3 homozygotes in gnomAD or ≥3 heterozygotes in well‐phenotyped family members." 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: "Functional studies show no damaging effect." The evidence for this variant shows: functional studies demonstrate a damaging (oncogenic) 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 family members." The evidence for this variant shows: no segregation data are 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 where only truncating variants cause disease." The evidence for this variant shows: PIK3CA pathogenic variants are often activating missense/indels. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to VCEP guidelines, the rule for BP2 is: "Observed in cis or trans with a known pathogenic variant in the same gene." 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 deletions/insertions in a repetitive region." The evidence for this variant shows: it is not located in a repetitive region. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: "For synonymous, intronic (non‐canonical) and UTR variants, two of three splicing tools predict no impact." The evidence for this variant shows: it is an in‐frame indel. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to VCEP guidelines, the rule for BP5 is: "Variant found in individual with an alternate molecular cause of disease." The evidence for this variant shows: no alternate molecular cause is reported. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source (e.g., ClinVar) reports the variant as benign." The evidence for this variant shows: it is not reported in ClinVar. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: "Synonymous or intronic (non‐canonical) variant with PhyloP <0.1." The evidence for this variant shows: it is an in‐frame indel. Therefore, this criterion is not applied.