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 Uncertain significance (1 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | -29 bp |
| Donor Loss (DL) | 0.0 | -56 bp |
| Acceptor Gain (AG) | 0.0 | -25 bp |
| Donor Gain (DG) | 0.0 | 80 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, 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.1171A>G is a missense variant (I391V), not a null variant. Therefore, this criterion is not applied.
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: I391V has not been reported as a pathogenic change at this residue. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 is: "Award the PS2 point if the variant is de novo with confirmed maternity and paternity and meets tissue fraction criteria for somatic mutations." The evidence for this variant shows: no de novo or parental testing data are available. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to VCEP guidelines, the rule for PS3 is: "Functional assays meeting the BMVCEP quality metrics and validation controls demonstrating a damaging effect on the gene or gene product." The evidence for this variant shows: no functional studies are available. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: "Case-control or case series data assigning points for phenotypic match in affected individuals absent from controls (PM2 required)." The evidence for this variant shows: no reported cases in the literature or series. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines, the rule for PM1 is: "Residues affecting critical functional domains provided in Table 4 for each gene (Supporting)." The evidence for this variant shows: I391 is not located within a known PIK3CA critical hotspot domain. 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 (Supporting)." The evidence for this variant shows: it is absent from gnomAD and other population databases. Therefore, this criterion is applied at Supporting strength.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: "Detected in trans with a pathogenic variant for recessive disorders (Moderate)." The evidence for this variant shows: PIK3CA-associated disease is dominantly acting and no trans data are available. 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 (Moderate)." The evidence for this variant shows: it is a missense change with no length alteration. 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 missense change is pathogenic (Moderate)." The evidence for this variant shows: no other pathogenic missense changes at residue I391 have been reported. 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 and maternity (Supporting)." 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 (Supporting)." 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 >3.09 for PIK3CA (Supporting)." The evidence for this variant shows: PIK3CA has a missense constraint z-score >3.09 in gnomAD. Therefore, this criterion is applied at Supporting strength.
PP3 (Not Applied)
According to standard ACMG guidelines, the rule for PP3 is: "Multiple computational tools predict a deleterious effect (Supporting)." The evidence for this variant shows: in silico tools (CADD, PolyPhen, REVEL, SpliceAI) predict a benign impact. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: "Patient phenotype is highly specific for a disease with a single genetic etiology (Supporting)." The evidence for this variant shows: no specific clinical phenotype information is provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports the variant as pathogenic (Supporting)." The evidence for this variant shows: ClinVar lists it as VUS, not pathogenic. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: "Allele frequency >0.0926% in population databases (Stand Alone)." The evidence for this variant shows: it is absent from population databases. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: "Allele frequency >0.0185% in population databases (Strong)." The evidence for this variant shows: it is absent from population databases. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: "Observed in ≥3 homozygotes in gnomAD or well-phenotyped family members (Strong)." 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: "Well-validated functional assays demonstrating no damaging effect (Strong)." The evidence for this variant shows: no benign functional 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 family members (Strong)." 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 (Supporting)." The evidence for this variant shows: PIK3CA pathogenic 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 trans with a pathogenic variant in a dominant disorder or in cis with a pathogenic variant (Supporting)." 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 repetitive regions without a known function (Supporting)." The evidence for this variant shows: it is a missense variant, not an in-frame indel. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: "Applicable only to synonymous, intronic (non-canonical) or non-coding UTR variants when ≥2 splice tools predict no impact (Supporting)." The evidence for this variant shows: it is a missense change, not eligible. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a gene with an alternative molecular basis for disease in the same individual (Supporting)." The evidence for this variant shows: no evidence of alternative etiology. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports the variant as benign (Supporting)." The evidence for this variant shows: no such reports. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: "Synonymous or intronic (non-canonical) variants with low conservation (PhyloP <0.1) (Supporting)." The evidence for this variant shows: it is a missense variant. Therefore, this criterion is not applied.