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) and as Likely benign (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) | 0.02 | -147 bp |
| Donor Loss (DL) | 0.0 | 498 bp |
| Acceptor Gain (AG) | 0.13 | -4 bp |
| Donor Gain (DG) | 0.04 | 128 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 it is a missense change (I311V) and not a null variant. Therefore, this criterion is not applied.
PS1 (Not Applied)
According to VCEP guidelines (no modification), 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 reported pathogenic variant causing I311V. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 is: "Award PS2_Strong if Criteria 1 AND Criteria 2 are fulfilled (de novo confirmed both maternity and paternity, etc.)." There is no de novo data for this variant. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to VCEP guidelines, the rule for PS3 is: "Well-established functional assay meeting VCEP quality metrics shows a damaging effect." No functional studies have been performed for I311V. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: "Statistical evidence of enrichment in affected individuals compared to controls (points system)." There are no reported patient cases for I311V. Therefore, this criterion is not applied.
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." I311 is not located in a known PIK3CA mutational hotspot or critical domain. Therefore, this criterion 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 it is extremely rare in gnomAD (MAF = 0.0012%, 3/249,446 alleles, no homozygotes). Therefore, this criterion is applied at Supporting strength because the variant is absent or rare in controls.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: "For recessive disorders, detected in trans with a pathogenic variant." PIK3CA-related 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 as a result of in-frame deletions/insertions." The I311V change does not alter protein length. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines (no modification), 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." No other pathogenic variant at codon 311 has been reported. Therefore, this criterion 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." No such data exist for this variant. 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." No segregation data are available. Therefore, this criterion is not applied.
PP2 (Supporting)
According to VCEP guidelines, the rule for PP2 is: "Supporting Missense constraint computed in ExAC/gnomAD was utilized. Award PP2 if the z-score > 3.09 (applicable to PIK3CA)." PIK3CA has a missense constraint z-score > 3.09 in gnomAD. Therefore, this criterion is applied at Supporting strength because the gene is missense constrained.
PP3 (Not Applied)
According to standard ACMG guidelines, the rule for PP3 is: "Multiple lines of computational evidence support a deleterious effect." In silico predictions for I311V are mixed and do not consistently predict a damaging effect. 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." No phenotype data are provided. 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 but evidence is unavailable." ClinVar submissions are conflicting (VUS and Likely benign). 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 variant MAF (0.0012%) is well below this threshold. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: "Strong: Allele frequency (>0.0185%)." The variant frequency is below this threshold. 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 well-phenotyped heterozygotes." No homozygotes or family observations exist. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: "Well-established functional assay shows no damaging effect." No such functional data exist. 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." No segregation data are available. 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 primarily truncating variants cause disease." PIK3CA pathogenic variants are gain-of-function missense changes. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: "Observed in cis or trans with a known pathogenic variant." No such data exist. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "In-frame indels in a repetitive region without known function." The variant is missense, not an in-frame indel. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: "Supporting: Applicable only to synonymous, intronic (non-canonical), or UTR variants when ≥2 splicing tools predict no impact." I311V is a missense variant. 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." No such information is provided. 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 but evidence is unavailable." ClinVar entries are conflicting and not exclusively benign. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: "Supporting: Synonymous or intronic variants (non-canonical) that are non-conserved." I311V is a missense variant. Therefore, this criterion is not applied.