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) | 0.03 | -80 bp |
| Donor Loss (DL) | 0.0 | 76 bp |
| Acceptor Gain (AG) | 0.0 | -31 bp |
| Donor Gain (DG) | 0.0 | 72 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 multi-exon deletion) in a gene where loss of function is a known mechanism of disease.' The evidence for this variant shows: it is a missense change (L648W), not a null variant. Therefore, this criterion is not applied because the variant type does not meet the rule for PVS1.
PS1 (Not Applied)
According to VCEP 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: no previously established pathogenic variant at codon L648 in PIK3CA. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 is: 'Award the PS2_Strong point if Criteria 1 AND Criteria 2 are fulfilled...' for high-confidence somatic mutations. The evidence for this variant shows: no parental or tissue segregation data are available. Therefore, this criterion is not applied due to lack of de novo or somatic confirmation data.
PS3 (Not Applied)
According to VCEP guidelines, the rule for PS3 is: 'Functional assays meeting SVI and BMVCEP quality metrics and validation controls...' The evidence for this variant shows: no functional studies have been performed. Therefore, this criterion is not applied due to absence of functional assay data.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: 'Points assigned for phenotype according to Table 2A, applied only if variant is absent from controls.' The evidence for this variant shows: no case reports or phenotype data. Therefore, this criterion is not applied due to lack of case-level 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: L648 is not located in a known critical hotspot or domain defined by the VCEP Table 4. 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 absent from gnomAD and other population databases (MAF = 0%). Therefore, this criterion is applied at Supporting strength because the variant is absent from controls.
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 disorders are not recessive and no in-trans data exist. 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 indels or stop-loss variants.' The evidence for this variant shows: it is a single amino acid substitution with no length change. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5 (Moderate) is: 'Different missense change at an amino acid residue where a pathogenic missense change has been established.' The evidence for this variant shows: no other pathogenic missense change at residue L648 is known. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to VCEP guidelines, the rule for PM6 is: 'Assumed de novo without confirmation of paternity and maternity.' The evidence for this variant shows: no de novo 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 are available. Therefore, this criterion is not applied.
PP2 (Supporting)
According to VCEP guidelines, the rule for PP2 is: 'Missense constraint computed in ExAC/gnomAD; award PP2 if the z-score > 3.09 (applicable to PIK3CA).' The evidence for this variant shows: PIK3CA has a missense z-score > 3.09, and this is a missense change. Therefore, this criterion is applied at Supporting strength.
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 predictions are mixed with a predominance of benign scores. 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 data are available. 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: no such reports exist in ClinVar or other databases. 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: MAF = 0% in 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: MAF = 0% in population databases. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 (Strong) is: '≥ 3 homozygotes in gnomAD or ≥ 3 heterozygotes in well-phenotyped family members.' The evidence for this variant shows: no observations in homozygous or well-phenotyped heterozygous individuals. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: 'Well-validated functional studies show no damaging effect.' The evidence for this variant shows: no functional studies. 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. 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 loss-of-function causes disease.' The evidence for this variant shows: PIK3CA disease mechanism is gain-of-function. 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 cis/trans data. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: 'In-frame indels in repetitive regions without a known function.' The evidence for this variant shows: this is a single amino acid substitution outside repeat regions. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: 'Applicable only to synonymous or non-coding variants when splicing prediction tools predict no impact.' The evidence for this variant shows: it is a missense change. 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: no such reports exist. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: 'Applicable only to synonymous or intronic variants with low conservation.' The evidence for this variant shows: it is a missense change. Therefore, this criterion is not applied.