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 PIK3CA H419_L422delinsM variant has been functionally characterized and identified as a statistically significant hotspot likely to be oncogenic, suggesting a damaging effect.
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) | 0.0 | 223 bp |
| Donor Loss (DL) | 0.0 | 154 bp |
| Acceptor Gain (AG) | 0.01 | 46 bp |
| Donor Gain (DG) | 0.0 | 330 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to standard ACMG guidelines, the rule for PVS1 is: "Null variant (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where loss of function is a known mechanism of disease." The evidence for this variant shows it is an in-frame delins (H419_L422delinsM), not a null variant; therefore, PVS1 is not applied.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: "Strong Strength: Strong No change. Modification Type: None." The evidence shows there is no previously reported variant with an identical amino acid change; therefore, PS1 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..." The evidence shows no parental or de novo data are available; therefore, PS2 is not applied.
PS3 (Strong)
According to VCEP guidelines, the rule for PS3 is: "Award PS3 if the functional assay meets the acceptability criteria delimited in (PMID: 31892348) with specifications added by the BMVCEP." The evidence shows well-established in vitro functional studies identify the H419_L422delinsM variant as a statistically significant hotspot likely to be oncogenic; therefore, PS3 is applied at Strong strength.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: "Points are assigned for phenotype according to (Table 2A)...Strength of evidence is determined by points according to (Table 2B)." The evidence for this variant shows no case or phenotype data with scored points; therefore, PS4 is not applied.
PM1 (Not Applied)
According to VCEP guidelines, the rule for PM1 is: "Supporting Strength: Residues affecting critical functional domains provided in Table 4 for each gene." The evidence shows H419_L422 is not listed as a VCEP-defined critical functional domain; 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 shows the variant is absent from gnomAD and other population databases; therefore, PM2 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 shows no recessive or trans configuration data; therefore, PM3 is not applied.
PM4 (Moderate)
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to inframe deletions/insertions in a non-repeat region." The evidence shows an in-frame delins replacing four amino acids with one (H419_L422delinsM) outside of a repetitive region; therefore, PM4 is applied at Moderate strength.
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 determined to be pathogenic has been seen before." The evidence shows this is an in-frame delins, not a novel missense substitution; therefore, PM5 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 shows no parental or de novo information; therefore, PM6 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 shows no family segregation data; therefore, PP1 is not applied.
PP2 (Not Applied)
According to VCEP guidelines, the rule for PP2 is: "Supporting - Missense constraint computed in ExAC/gnomAD; award if z-score > 3.09." The evidence shows this is an in-frame delins rather than a missense variant; therefore, PP2 is not applied.
PP3 (Not Applied)
According to standard ACMG guidelines, the rule for PP3 is: "Multiple lines of computational evidence support a deleterious effect on the gene or gene product." The evidence shows in silico tools and SpliceAI predict no impact on splicing or function; therefore, PP3 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." No phenotype specificity data are available; therefore, PP4 is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source recently reports variant as pathogenic." No such report exists in ClinVar or other 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 shows the variant frequency is 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 shows the variant frequency is 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 members." The evidence shows no such occurrences; therefore, BS2 is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: "Strong: Well-established in vitro or in vivo functional studies show no damaging effect." The evidence shows functional studies demonstrate a damaging, oncogenic effect; therefore, BS3 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." No segregation data are available; therefore, BS4 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." PIK3CA disease mechanism is gain-of-function; therefore, BP1 is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant." No such data exist; therefore, BP2 is not applied.
BP3 (Not Applied)
According to VCEP guidelines, the rule for BP3 is: "Supporting: In-frame indels in a repetitive region without known function." The region spanning H419-L422 is not repetitive; therefore, BP3 is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: "Supporting: Synonymous, intronic (non-canonical), or UTR variants predicted by two of three splicing tools to have no impact." This variant is a coding in-frame delins, not eligible; therefore, BP4 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." No such reports exist; therefore, BP5 is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign." No such source exists; therefore, BP6 is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: "Supporting: Synonymous, intronic (non-canonical), or UTR variants with low conservation." This variant is not synonymous or intronic; therefore, BP7 is not applied.