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) | 0.02 | 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 (Very Strong)
According to standard ACMG guidelines, the rule for PVS1 is: 'Null Variant (nonsense, fs, start codon, splicing +1/2, startgain, single or multi-exon deletion) in a gene where loss-of-function is a known mechanism of disease'. The evidence for this variant shows: NM_006218.4:c.1265del causes a frameshift (p.L422Wfs*6) leading to a premature stop codon in a non-terminal exon of PIK3CA. Therefore, this criterion is applied at Very Strong strength because frameshift variants producing premature truncation in PIK3CA result in loss-of-function, a known disease mechanism.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: 'Strong: same amino acid change as a known pathogenic variant, different nucleotide change (no modification)'. The evidence for this variant shows: L422Wfs*6 is a novel frameshift, not the same amino acid change as any known pathogenic variant. Therefore, PS1 is not applied because the variant does not meet the requirement of encoding the same amino acid change by a different nucleotide substitution.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 is: 'Strong: Award PS2_Strong if Criteria 1 AND Criteria 2 are fulfilled (confirmed de novo in both parental samples and mosaic presence in affected tissue)'. The evidence for this variant shows: no parental or affected tissue segregation data are provided. Therefore, PS2 is not applied due to lack of de novo confirmation data.
PS3 (Not Applied)
According to VCEP guidelines, the rule for PS3 is: 'Strong: Follow recommendations set forth by the SVI in conjunction with specifications added by the BMVCEP for quality metrics and minimum validation controls required'. The evidence for this variant shows: no functional studies have been performed on PIK3CA L422Wfs*6. Therefore, PS3 is not applied due to absence of well-established functional assay data.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: 'Very Strong: Points are assigned for phenotype according to Table 2A, applicable only if variant is absent from controls (PM2) and ≥16 points are achieved'. The evidence for this variant shows: no reported cases or phenotype correlation data. Therefore, PS4 is not applied due to lack of clinical case evidence.
PM1 (Not Applied)
According to VCEP guidelines, the rule for PM1 is: 'Supporting: Residues affecting critical functional domains provided in Table 4 for each gene'. The evidence for this variant shows: the frameshift affects residue L422 but domain-specific critical residue tables do not list this region. Therefore, PM1 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, PM2 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: 'Moderate: For recessive disorders, detected in trans with a pathogenic variant'. The evidence for this variant shows: PIK3CA-associated conditions are dominantly acting and no trans findings are available. Therefore, PM3 is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: 'Moderate: Protein length changes due to in-frame indels or stop-loss variants'. The evidence for this variant shows: this is a frameshift leading to premature truncation, not an in-frame alteration. Therefore, PM4 is not applied.
PM5 (Not Applied)
According to standard ACMG guidelines, the rule for PM5 is: 'Moderate: Novel missense change at an amino acid residue where a different missense change is pathogenic'. The evidence for this variant shows: this is a frameshift, not a missense variant. Therefore, PM5 is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: 'Supporting: Assumed de novo, without confirmation of paternity and maternity'. The evidence for this variant shows: no de novo assumption or parental data are provided. Therefore, PM6 is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines, the rule for PP1 is: 'Supporting: Co-segregation with disease in multiple affected family members'. The evidence for this variant shows: no family segregation data are available. Therefore, PP1 is not applied.
PP2 (Not Applied)
According to VCEP guidelines, the rule for PP2 is: 'Supporting: Missense constraint computed in ExAC/gnomAD with z-score >3.09 applied to PIK3CA'. The evidence for this variant shows: it is a frameshift, not a missense variant. Therefore, PP2 is not applied.
PP3 (Not Applied)
According to standard ACMG guidelines, the rule for PP3 is: 'Supporting: Multiple lines of computational evidence support a deleterious effect'. The evidence for this variant shows: in silico tools are conflicting and SpliceAI score is 0.07 below significance threshold. Therefore, PP3 is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: 'Supporting: 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 data provided. Therefore, PP4 is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: 'Supporting: Reports from reputable source but without available evidence'. The evidence for this variant shows: no entries in ClinVar or other reputable databases. Therefore, PP5 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, BA1 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, BS1 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 occurrences in healthy individuals. Therefore, BS2 is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: 'Strong/Supporting: Well-established functional studies show no damaging effect'. The evidence for this variant shows: no functional studies have been performed. Therefore, BS3 is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, the rule for BS4 is: 'Strong: Lack of segregation in affected family members'. The evidence for this variant shows: no segregation data are available. Therefore, BS4 is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: 'Supporting: Missense variant in gene for which primarily truncating variants cause disease'. The evidence for this variant shows: it is truncating. Therefore, BP1 is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: 'Supporting: Observed in trans with a pathogenic variant'. The evidence for this variant shows: no phasing data available. Therefore, BP2 is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: 'Supporting: In-frame indel in a repetitive region without known function'. The evidence for this variant shows: this is a non-repetitive frameshift. Therefore, BP3 is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: 'Supporting: Synonymous or intronic variants with no impact on splicing predicted by ≥2 tools'. The evidence for this variant shows: it is coding frameshift, not synonymous/intronic. Therefore, BP4 is not applied.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 is: 'Supporting: Variant found in a case with an alternate molecular basis for disease'. The evidence for this variant shows: no such context is provided. Therefore, BP5 is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: 'Supporting: Reputable source reports variant as benign without evidence'. The evidence for this variant shows: no such reports exist. Therefore, BP6 is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: 'Supporting: Synonymous or intronic variant at non-conserved nucleotide (PhyloP <0.1)'. The evidence for this variant shows: it is a frameshift, not synonymous/intronic. Therefore, BP7 is not applied.