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
OpenFunctional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | -9 bp |
| Donor Loss (DL) | 0.0 | -68 bp |
| Acceptor Gain (AG) | 0.01 | -16 bp |
| Donor Gain (DG) | 0.0 | -3 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 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.2953T>A results in a missense change (Y985N) and variant consequence/type is unknown. Therefore, this criterion is not applied because the variant is not a null variant or loss-of-function type.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: "Strong: Same amino acid change as a previously established pathogenic variant regardless of nucleotide change." The evidence for this variant shows: there is no previously established pathogenic variant resulting in Y985N. Therefore, this criterion is not applied because the variant does not match a known pathogenic amino acid change.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 is: "Strong: Award the PS2_Strong point if Criteria 1 AND Criteria 2 are fulfilled (confirmed de novo in patient with disease and confirmed in tissue heterogeneity context)." The evidence for this variant shows: no data on de novo occurrence or somatic tissue fraction. Therefore, this criterion is not applied due to lack of de novo or tissue evidence.
PS3 (Not Applied)
According to VCEP guidelines, the rule for PS3 is: "Strong: Functional assay meets the acceptability criteria delimited in (PMID: 31892348) with VCEP specifications." The evidence for this variant shows: no functional characterization studies have been performed. Therefore, this criterion is not applied because functional data are absent.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: "Very Strong: ≥16 phenotype points for cases absent from controls; Strong: 3.5–15.75 points; Moderate: 1.5–3.25 points; Supporting: 0.5–1.25 points." The evidence for this variant shows: no case reports or phenotype data. Therefore, this criterion is not applied due to absence of case-level phenotype 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 position Y985 has not been annotated as within a defined critical functional domain. Therefore, this criterion is not applied because domain mapping information is unavailable.
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: NM_006218.4:c.2953T>A is not present in gnomAD or other population databases (MAF = 0%). Therefore, this criterion 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: "For recessive disorders, detected in trans with a pathogenic variant." The evidence for this variant shows: no data on cis/trans configuration with other PIK3CA variants. Therefore, this criterion is not applied due to absence of trans evidence.
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: NM_006218.4:c.2953T>A is a missense substitution without protein length alteration. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5 is: "Moderate: Novel missense change at an amino acid residue where a different missense change has been established as pathogenic." The evidence for this variant shows: no other pathogenic missense variant at residue Y985 has been reported. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: "Presumed de novo, without confirmation of paternity and maternity." 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: "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 (Not Applied)
According to VCEP guidelines, the rule for PP2 is: "Supporting: Missense constraint computed in ExAC/gnomAD with z-score >3.09." The evidence for this variant shows: no ExAC/gnomAD z-score has been provided. Therefore, this criterion is not applied due to missing missense constraint data.
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: the majority of in silico tools predict benign impact (SIFT, PolyPhen, MetaSVM benign; REVEL 0.45; low CADD; SpliceAI 0.01). Therefore, this criterion is not applied because computational evidence does not support deleterious effect.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: "Patient phenotype or family history is highly specific for gene." The evidence for this variant shows: no phenotype or clinical presentation data are provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source recently reports variant as pathogenic." The evidence for this variant shows: not present in ClinVar or other reputable databases. Therefore, this criterion 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: allele frequency is 0% in population databases. Therefore, this criterion 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: allele frequency is 0% in population databases. Therefore, this criterion 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 individuals." The evidence for this variant shows: no homozygotes or heterozygotes reported. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: "Strong: Well-validated functional studies show no damaging effect; Supporting: less robust functional evidence." The evidence for this variant shows: no functional studies are available. 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 for which primarily loss-of-function causes disease." The evidence for this variant shows: PIK3CA disease mechanism is often gain-of-function, and this is a missense variant. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to VCEP guidelines, the rule for BP2 is: "Supporting: Observed in cis or trans with a known pathogenic variant in the same gene." The evidence for this variant shows: no information on cis/trans status with other variants. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "In-frame insertions/deletions in repetitive regions without known function." The evidence for this variant shows: this is a single nucleotide substitution. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: "Supporting: Applicable only to synonymous, intronic (except canonical splice sites), or UTR variants when two of three splice tools predict no impact." The evidence for this variant shows: Y985N is a missense change. Therefore, this criterion is not applied under VCEP specifications.
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 information on alternative molecular findings. 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: not present in ClinVar or similar sources. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: "Supporting: For synonymous or intronic positions (non-canonical) with PhyloP <0.1." The evidence for this variant shows: Y985N is a missense substitution. Therefore, this criterion is not applied.