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 Likely pathogenic (1 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The PIK3CA N1068Kfs*5 variant has been functionally characterized and shown to have a damaging effect. This frameshift mutation results in increased cell proliferation, migration, and Akt phosphorylation compared to wild-type PIK3CA. It also enhances transformation ability in various cell lines, indicating an activating and likely oncogenic role.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | None bp |
| Donor Loss (DL) | 0.0 | None bp |
| Acceptor Gain (AG) | 0.0 | None bp |
| Donor Gain (DG) | 0.0 | None 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) in a gene where loss of function is a known mechanism of disease." The evidence for this variant shows: PIK3CA loss of function is not an established disease mechanism and this frameshift variant functions via gain-of-function. Therefore, this criterion is not applied.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: "Strong strength: same amino acid change as an established pathogenic variant." The evidence for this variant shows: N1068Kfs*5 results in a novel frameshift not matching any known pathogenic amino acid change. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 is: "Strong: award if criteria 1 and 2 are fulfilled; Moderate: award if criteria 1 is fulfilled or if parents unavailable but criteria 2 fulfilled." The evidence for this variant shows: no de novo or somatic allele fraction data in parental and tissue samples. Therefore, this criterion is not applied.
PS3 (Strong)
According to VCEP guidelines, the rule for PS3 is: "Strong strength: functional assay meets acceptability criteria as per SVI and BMVCEP specifications (PMID:31892348)." The evidence for this variant shows: well-controlled in vitro assays demonstrate increased cell proliferation, migration, and Akt phosphorylation compared to wild-type, consistent with an activating effect. Therefore, this criterion is applied at Strong strength.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: "Assign points for phenotype if variant absent from controls (PM2), with ≥16 points for Very Strong, 3.5–15.75 for Strong, etc." The evidence for this variant shows: no reported phenotype case data available to assign points. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines, the rule for PM1 is: "Supporting strength: residues affecting critical functional domains as provided in Table 4 for each gene." The evidence for this variant shows: position N1068 is not listed in the established PIK3CA functional domain hotspots. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 is: "Supporting strength: absent or rare from controls in ethnically-matched cohort population samples." The evidence for this variant shows: not observed in gnomAD or 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: not relevant to a recessive inheritance context in PIK3CA. 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: the variant is a frameshift, not an in-frame alteration. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5 is: "Moderate strength: novel missense change at an amino acid residue where a different missense change is pathogenic." The evidence for this variant shows: it is a frameshift variant, not a missense change. 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 provided. 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 (Not Applied)
According to VCEP guidelines, the rule for PP2 is: "Supporting strength: missense constraint z-score >3.09 applies to PIK3CA." The evidence for this variant shows: variant is frameshift, not 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 on the gene." The evidence for this variant shows: computational in silico tools were inconclusive. 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 specific patient 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 without accessible evidence." The evidence for this variant shows: ClinVar lists as Likely pathogenic, but PP5 is generally discouraged. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: "Stand Alone strength: allele frequency >0.0926%." The evidence for this variant shows: not present in population databases. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: "Strong strength: allele frequency >0.0185%." The evidence for this variant shows: not present in population databases. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: "Strong strength: ≥3 homozygotes or heterozygotes in well-phenotyped individuals." The evidence for this variant shows: not observed in gnomAD/clinical cohorts. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: "Strong strength: well-established functional studies show no damaging effect." The evidence for this variant shows: functional studies demonstrate damaging activating 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 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 only truncating variants cause disease." The evidence for this variant shows: disease mechanism is gain-of-function, and this is truncating. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a known pathogenic variant in the same gene." The evidence for this variant shows: no data on cis/trans configuration. 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 without a known function." The evidence for this variant shows: frameshift variant, not an in-frame indel in a repetitive region. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: "Supporting strength: synonymous, intronic, or non-coding variants with two of three splice tools predicting no impact." The evidence for this variant shows: not a synonymous/intronic/UTR variant. 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 alternate molecular basis reported. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports benign classification without evidence." The evidence for this variant shows: no such benign classification exists. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: "Supporting strength: synonymous or intronic variants at non-conserved positions." The evidence for this variant shows: not a synonymous/intronic variant. Therefore, this criterion is not applied.