PIK3CA c.1049A>G, p.Asp350Gly
NM_006218.4:c.1049A>G
COSM271786
Population Frequency
0.0 in 100,000
Rare
ClinVar Classification
Pathogenic
1 publications
REVEL Score
0.664
Uncertain (High)
COSMIC Recurrence
13 occurrences
No Criteria Applied
Classification Evidence
Detailed Information
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.1049A>G
Protein Change
D350G
Location
Exon 5
(Exon 5 of 21)
5'
Exon Structure (21 total)
3'
Functional Consequence
Missense Variant
Related Variants
ClinVar reports other pathogenic variants at position 350: D350N
Alternate Identifiers
COSM271786
Variant interpretation based on transcript NM_006218.4
Clinical Evidence
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.0005%
0.001%
0.01%
0.05%
1%+
ACMG Criteria Applied
PM2
This variant is rare in the population (0.000000% MAF).
Classification
1 publications
Pathogenic
Based on 2 submitter reviews in ClinVar
Submitter Breakdown
Pathogenic
Likely Pathogenic
VUS
Likely Benign
Benign
Publications
1 publications
Show publication details
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratories) and as Pathogenic (1 clinical laboratories).
Functional Domain
Hotspot Status
Hotspot
PM1
Mutation Count
36
Reported mutations in this domain
0
50
100+
Domain Summary
This variant is located in a mutational hotspot or critical domain (36 mutations).
PM1 criterion applied: Located in a mutational hot spot and/or critical and well-established functional domain.
Related Variants in This Domain
ClinVar reports other pathogenic variants at position 350: D350N
PM5 criterion applied: Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
Functional Studies
Summary
The PIK3CA D350G variant has been functionally characterized and demonstrates a damaging effect. It is located in the C2 domain of the PIK3CA protein and results in increased phosphorylation of Akt, indicating activation of downstream signaling pathways. This variant also shows increased transformation ability in cell lines compared to the wild-type protein, supporting its oncogenic potential. Additionally, other pathogenic variants at the same codon have been reported, fulfilling the PM5 ACMG criterion.
Computational Evidence
Pathogenicity Predictions
REVEL Score
0.664
0.664
Likely Benign
0.0
Uncertain (Low)
0.2
Uncertain (Med)
0.5
Likely Pathogenic
0.75
REVEL scores ≥ 0.75 are considered strong evidence of pathogenicity (PP3)
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria
VCEP Guidelines
PS3
PS3 (Strong)
According to VCEP guidelines: 'Award PS3 if the functional assay meets the acceptability criteria delimited in (PMID: 31892348) with specifications added by the BMVCEP.' The evidence for this variant shows: The PIK3CA D350G variant has been functionally characterized and demonstrates a damaging effect, indicating activation of downstream signaling pathways and increased transformation ability in cell lines. Therefore, this criterion meets the requirements because strong functional evidence supports the damaging effect of the variant.
PM1
PM1 (Supporting)
Strength Modified
According to VCEP guidelines: 'Residues affecting critical functional domains provided in Table 4 for each gene.' The evidence for this variant shows: The D350G change occurs in the C2 domain of PIK3CA, which is critical for its function. Therefore, this criterion meets the requirements because the variant is located in a well-established functional domain without benign variation.
PM2
PM2 (Supporting)
Strength Modified
According to VCEP guidelines: 'Absent/rare from controls in an ethnically-matched cohort population sample (≥1).' The evidence for this variant shows: The variant is not found in population databases such as gnomAD, indicating it is absent from controls. Therefore, this criterion meets the requirements because the variant is not present in the general population.
PM5
PM5 (Moderate)
According to standard ACMG guidelines: 'Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen.' The evidence for this variant shows: Other pathogenic variants have been reported at the same codon (D350) in PIK3CA. Therefore, this criterion meets the requirements because it fulfills the criteria for PM5.
PP5
PP5 (Supporting)
According to standard ACMG guidelines: 'Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.' The evidence for this variant shows: The variant has been reported as pathogenic in ClinVar by one clinical laboratory. Therefore, this criterion meets the requirements because it is supported by a reputable source.
BP4
BP4 (Supporting)
According to VCEP guidelines: 'Award BP4 for a synonymous, intronic positions (except canonical splice sites) or non-coding variants in the UTRs, if two out of three of the splicing prediction tools predicted no impact on splicing function.' The evidence for this variant shows: Insufficient in silico prediction data; SpliceAI predicts no impact on splicing. Therefore, this criterion meets the requirements because the variant does not significantly impact splicing.