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 variant PIK3CA L422Wfs*6 is a truncating mutation in the PIK3CA gene, which is an oncogene. Truncating mutations in oncogenes are typically nonfunctional. However, no specific functional characterization data for this variant is available.
Click on previews to view full database entries. External databases may require institutional access.
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.02 | 215 bp |
| Donor Loss (DL) | 0.0 | 146 bp |
| Acceptor Gain (AG) | 0.07 | 38 bp |
| Donor Gain (DG) | 0.0 | 322 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 multiexon deletion) in a gene where loss‐of‐function is a known mechanism of disease." The evidence for this variant shows: c.1265del is a frameshift causing early truncation (L422Wfs*6), but PIK3CA disease mechanism is gain‐of‐function rather than loss‐of‐function. Therefore, this criterion is not applied because LOF is not a known mechanism of disease for PIK3CA.
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: it is a frameshift variant, not a single amino acid substitution matching a known pathogenic missense. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 (Strong) requires confirmed de novo occurrence with parental testing and evidence of mosaicism patterns in tissues. The evidence for this variant shows: no information on parental or tissue allele fractions, no de novo data. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to VCEP guidelines, the rule for PS3 requires well‐validated functional assays demonstrating a damaging effect. The evidence for this variant shows: no functional study data specific to L422Wfs*6. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 requires aggregate case‐control or case‐level data demonstrating enrichment in affected individuals (with points thresholds). The evidence for this variant shows: no published case reports or case‐control data. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines, the rule for PM1 (Supporting) is: "Variant affects a residue in a critical functional domain/hotspot as defined in PIK3CA-specific Table 4." The evidence for this variant shows: position L422 is not within the known PIK3CA hotspot or critical domain. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 (Supporting) is: "Absent/rare from controls in an ethnically-matched cohort population sample." The evidence for this variant shows: not present in gnomAD or other control 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-associated conditions are not recessive and no trans data. 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 or stop-loss variants." The evidence for this variant shows: this is a frameshift predicted to trigger premature truncation, not an in-frame indel or stop-loss. 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: it is a frameshift, 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, 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. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to VCEP guidelines, the rule for PP2 is: "Missense variant in a gene with low rate of benign missense variation (z-score >3.09)." The evidence for this variant shows: it is a frameshift, not missense. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: "Computational evidence supports a deleterious effect." The evidence for this variant shows: as a frameshift, in silico splicing predictions are not applicable and no strong computational data. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: "Patient's phenotype is highly specific for a single gene disorder." 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 without available evidence." The evidence for this variant shows: not reported in ClinVar or other sources. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 (Stand Alone) is: "Allele frequency >0.0926%." The evidence for this variant shows: absent from population databases. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 (Strong) is: "Allele frequency >0.0185%." The evidence for this variant shows: absent from population databases. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 (Strong) is: "Observed in ≥3 unaffected individuals or homozygotes." 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 requires well-validated functional assays showing no damaging effect. The evidence for this variant shows: no functional assay data. 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 a gene for which primarily truncating variants cause disease." The evidence for this variant shows: it is truncating, not missense. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: "Observed in cis with a pathogenic variant." 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 indel in a repetitive region without a known function." The evidence for this variant shows: it is a frameshift, not an in-frame indel. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: "Computational evidence suggests no impact on gene or gene product." The evidence for this variant shows: as a frameshift, computational predictions do not indicate benign effect. 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 alternative molecular basis for disease." The evidence for this variant shows: no information on alternative causes. 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 without available evidence." The evidence for this variant shows: not reported as benign. 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 low conservation." The evidence for this variant shows: it is not synonymous. Therefore, this criterion is not applied.