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 N345D variant has not been functionally characterized, and its effect on protein function remains unknown.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | 2 bp |
| Donor Loss (DL) | 0.0 | 2 bp |
| Acceptor Gain (AG) | 0.13 | -106 bp |
| Donor Gain (DG) | 0.09 | 26 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 multiexon deletion) in a gene where loss of function is a known mechanism of disease is Very Strong.' The evidence for this variant shows: it is a missense change (c.1033A>G; p.N345D), not a null variant. Therefore, this criterion is not applied at any strength.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: 'Strong Strength: Strong. No change.' The evidence for this variant shows: there is no other nucleotide change resulting in the same amino acid substitution (p.N345D) previously established as pathogenic. Therefore, this criterion is not applied at any strength.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 is: 'Strong Strength: Strong Award the PS2_Strong point if Criteria 1 AND Criteria 2 are fulfilled (de novo in confirmed maternity/paternity and mosaicism evidence).' The evidence for this variant shows: no de novo or parental origin data are available. Therefore, this criterion is not applied at any strength.
PS3 (Not Applied)
According to VCEP guidelines, the rule for PS3 is: 'Strong Strength: Strong Follow recommendations set forth by the SVI with specified quality metrics for functional assays.' The evidence for this variant shows: no well‐established functional studies have been performed for p.N345D in PIK3CA. Therefore, this criterion is not applied at any strength.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: 'Very Strong/Strong/Moderate/Supporting based on case-level phenotype points when variant is absent/rare (PM2).' The evidence for this variant shows: no published case‐control or case series data exist for p.N345D. Therefore, this criterion is not applied at any strength.
PM1 (Supporting)
According to VCEP guidelines, the rule for PM1 is: 'Supporting Strength: Supporting Residues affecting critical functional domains provided in Table 4 for each gene.' The evidence for this variant shows: residue N345 lies within the PIK3CA helical domain, a well‐established functional domain. Therefore, this criterion is applied at Supporting strength because the variant affects a critical domain without benign variation.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 is: 'Supporting Strength: Supporting Absent/rare from controls in an ethnically-matched cohort population sample (≥1).' The evidence for this variant shows: p.N345D 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 is Moderate.' The evidence for this variant shows: no recessive or trans-phase data are available. Therefore, this criterion is not applied at any strength.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: 'Protein length changes as a result of in-frame indels or stop-loss variants are Moderate.' The evidence for this variant shows: p.N345D is a missense substitution, not a length-altering change. Therefore, this criterion is not applied at any strength.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5 is: 'Moderate Strength: Moderate. No change.' The evidence for this variant shows: there is no other distinct missense change at codon 345 previously established as pathogenic. Therefore, this criterion is not applied at any strength.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: 'Assumed de novo, but without confirmation of paternity and maternity is Moderate.' The evidence for this variant shows: no de novo data are available. Therefore, this criterion is not applied at any strength.
PP1 (Not Applied)
According to standard ACMG guidelines, the rule for PP1 is: 'Co-segregation with disease in multiple affected family members is Supporting.' The evidence for this variant shows: no family segregation data are available. Therefore, this criterion is not applied at any strength.
PP2 (Supporting)
According to VCEP guidelines, the rule for PP2 is: 'Supporting Strength: Supporting Missense constraint computed in ExAC/gnomAD was utilized. Award PP2 if the z‐score > 3.09.' 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 because the gene is constrained for missense variation.
PP3 (Not Applied)
According to standard ACMG guidelines, the rule for PP3 is: 'Multiple lines of computational evidence support a deleterious effect is Supporting.' The evidence for this variant shows: in silico predictions are mixed (PolyPhen-2 and MetasVM predict damaging, but CADD is low and SpliceAI shows no splice impact). Therefore, this criterion is not applied at any strength.
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 is Supporting.' The evidence for this variant shows: no phenotype or clinical correlation data are provided. Therefore, this criterion is not applied at any strength.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source reports variant as pathogenic without available evidence is Supporting.' The evidence for this variant shows: no such reports exist. Therefore, this criterion is not applied at any strength.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: 'Stand Alone Strength: Stand Alone Allele frequency (>0.0926%).' The evidence for this variant shows: allele frequency is 0%, below the threshold. Therefore, this criterion is not applied at any strength.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: 'Strong Strength: Strong Allele frequency (>0.0185%).' The evidence for this variant shows: allele frequency is 0%, below the threshold. Therefore, this criterion is not applied at any strength.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: 'Strong Strength: Strong Award BS2 if ≥3 homozygotes present in gnomAD or ≥3 heterozygous in well‐phenotyped family members.' The evidence for this variant shows: no such occurrences. Therefore, this criterion is not applied at any strength.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: 'Strong/Supporting Strength: Follow recommendations for functional assays showing no damaging effect.' The evidence for this variant shows: no functional assays demonstrating benign effect. Therefore, this criterion is not applied at any strength.
BS4 (Not Applied)
According to standard ACMG guidelines, the rule for BS4 is: 'Lack of segregation in affected members of a family is Strong for benign.' The evidence for this variant shows: no segregation data in unaffected family members. Therefore, this criterion is not applied at any strength.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: 'Missense variant in a gene for which only truncating variants are known to cause disease is Supporting.' The evidence for this variant shows: PIK3CA disease mechanism includes gain‐of‐function missense variants. Therefore, this criterion is not applied at any strength.
BP2 (Not Applied)
According to VCEP guidelines, the rule for BP2 is: 'Supporting Strength: Observed in cis or trans with a known pathogenic variant in the same gene.' The evidence for this variant shows: no such observations. Therefore, this criterion is not applied at any strength.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: 'In-frame insertions/deletions in repetitive regions without a known function is Supporting.' The evidence for this variant shows: missense substitution, not an in-frame indel. Therefore, this criterion is not applied at any strength.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: 'Supporting Strength: Applicable only to synonymous/intronic/UTR variants when ≥2 of 3 splicing tools predict no impact.' The evidence for this variant shows: it is a missense variant. Therefore, this criterion is not applied at any strength.
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 is Supporting.' The evidence for this variant shows: no such case reports. Therefore, this criterion is not applied at any strength.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source reports variant as benign without available evidence is Supporting.' The evidence for this variant shows: no such reports. Therefore, this criterion is not applied at any strength.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: 'Supporting Strength: For synonymous/intronic/UTR variants with low conservation (PhyloP <0.1).' The evidence for this variant shows: it is missense. Therefore, this criterion is not applied at any strength.