PIK3CA c.1033A>G, p.Asn345Asp
NM_006218.4:c.1033A>G
COSMIC ID: COSM6922462
Likely Pathogenic
The variant p.N345D in PIK3CA is absent from population databases (PM2_Supporting), occurs in a critical functional domain (PM1_Supporting), and the gene is constrained for missense changes (PP2_Supporting). No moderate or strong evidence is available, leading to classification as a Variant of Uncertain Significance (VUS).
ACMG/AMP Criteria Applied
PM1
PM2
PP2
Genetic Information
Gene & Transcript Details
Gene
PIK3CA
Transcript
NM_006218.4
MANE Select
Total Exons
21
Strand
Forward (+)
Reference Sequence
NC_000003.11
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_006218.2 | Alternative | 21 exons | Forward |
| NM_006218.3 | Alternative | 21 exons | Forward |
Variant Details
HGVS Notation
NM_006218.4:c.1033A>G
Protein Change
N345D
Location
Exon 5
(Exon 5 of 21)
5'Exon Structure (21 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 345: N345S, N345T, N345K
Alternate Identifiers
COSM6922462
Variant interpretation based on transcript NM_006218.4
Genome Browser
Loading genome browser...
HGVS InputNM_006218:c.1033A>G
Active Tracks
ConservationRefSeqClinVargnomAD
Navigation tips: Use mouse to drag and zoom. Click on features for details.
Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Unknown
Publications (0)
No publication details.
Clinical Statement
Functional Impact
Functional Domain
Hotspot Status
Hotspot
PM1
Mutation Count
686
Reported mutations in this domain
050100+
Domain Summary
This variant is located in a mutational hotspot or critical domain (686 mutations).
PM1 criterion applied.
Related Variants in This Domain
ClinVar reports other pathogenic variants at position 345: N345S, N345T, N345K
PM5 criterion applied.
Functional Summary
The PIK3CA N345D variant has not been functionally characterized, and its effect on protein function remains unknown.
Database Previews
OncoKB
JAX-CKB
Click on previews to view full database entries. External databases may require institutional access.
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.565
0.565
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Pathogenic:
polyphen_prediction: probably_damagingmetasvm: Dmetalr: Dprimateai: D
Benign:
CADD: 4.82
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
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
PS1 (Not Applied) Strength Modified
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
PS2 (Not Applied) Strength Modified
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
PS3 (Not Applied) Strength Modified
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
PS4 (Not Applied) Strength Modified
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
PM1 (Supporting) Strength Modified
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
PM2 (Supporting) Strength Modified
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
PM3 (Not Applied) Strength Modified
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
PM4 (Not Applied) Strength Modified
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
PM5 (Not Applied) Strength Modified
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
PM6 (Not Applied) Strength Modified
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
PP1 (Not Applied) Strength Modified
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
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
PP3 (Not Applied) Strength Modified
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
PP4 (Not Applied) Strength Modified
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
PP5 (Not Applied) Strength Modified
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
BA1 (Not Applied) Strength Modified
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
BS1 (Not Applied) Strength Modified
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
BS2 (Not Applied) Strength Modified
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
BS3 (Not Applied) Strength Modified
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
BS4 (Not Applied) Strength Modified
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
BP1 (Not Applied) Strength Modified
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
BP2 (Not Applied) Strength Modified
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
BP3 (Not Applied) Strength Modified
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
BP4 (Not Applied) Strength Modified
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
BP5 (Not Applied) Strength Modified
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
BP6 (Not Applied) Strength Modified
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
BP7 (Not Applied) Strength Modified
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.