PIK3CA c.3060_3062delinsGTG, p.Tyr1021Cys
NM_006218.4:c.3060_3062delinsGTG
Population Frequency
0.0 in 100,000
Rare
ClinVar Classification
Unknown
0 publications
REVEL Score
N/A
Not Available
COSMIC Recurrence
0 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.3060_3062delinsGTG
Protein Change
Y1021C
Location
Exon 21
(Exon 21 of 21)
5'
Exon Structure (21 total)
3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 1021: Y1021H
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 not present in gnomAD (PM2 criteria applies).
Classification
Unknown
Publications
0 publications
Clinical Statement
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
ClinVar reports other pathogenic variants at position 1021: Y1021H
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 Y1021C variant has been functionally characterized with conflicting results. In Ba/F3 cells, it demonstrated an activating effect by increasing growth factor-independent proliferation. However, in MCF10A cells and a transgenic mouse model, it showed a neutral effect, failing to induce growth factor-independent proliferation or glioblastoma formation. The variant has not been biochemically characterized, and its precise impact on PIK3CA protein function remains unclear.
Computational Evidence
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria
VCEP Guidelines
PVS1
PVS1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PVS1 is: 'PVS1: 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 shows that PIK3CA disease mechanism is gain-of-function rather than loss-of-function. Therefore, this criterion is not applied because LoF is not a known mechanism for PIK3CA.
PS1
PS1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: 'PS1: Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.' The evidence shows no previously established pathogenic variant yields the same Y1021C amino acid change. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: 'PS2: De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.' Parental genotype and de novo status data are unavailable. Therefore, PS2 is not applied.
PS3
PS3 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PS3 is: 'Award PS3 if the functional assay meets acceptability criteria delineated by VCEP and Brain Malformation Group, with strong controls and validation.' The available functional studies are conflicting, showing activation in Ba/F3 cells but neutral effects in MCF10A cells and mouse models. Therefore, PS3 is not applied due to insufficient and conflicting functional evidence.
PS4
PS4 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PS4 is: 'Assign strength based on case-level or case-control data points if variant is absent/rare in controls (PM2).' No case-level or case-control phenotype data are available. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PM1 is: 'Supporting: Residues affecting critical functional domains (as defined in Table 4).' Y1021 is not located within a defined critical hotspot domain for PIK3CA. Therefore, PM1 is not applied.
PM2
PM2 (Supporting)
Strength Modified
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 population databases (gnomAD MAF = 0%). Therefore, PM2 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: 'PM3: Detected in trans with a pathogenic variant in recessive disorders.' PIK3CA-related conditions are dominant and no trans data are available. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: 'PM4: Protein length changes (in-frame indels or stop-loss) in a non-repeat region.' This variant is a missense substitution without length change. Therefore, PM4 is not applied.
PM5
PM5 (Moderate)
According to VCEP guidelines, the rule for PM5 is: 'Moderate: Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen.' The evidence indicates Y1021C is novel, and other pathogenic missense variants at residue 1021 have been reported. Therefore, PM5 is applied at Moderate strength because the residue is a known pathogenic hotspot for missense changes.
PM6
PM6 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: 'PM6: Assumed de novo, without confirmation of paternity and maternity.' No de novo data are available. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: 'PP1: Cosegregation with disease in multiple affected family members.' No segregation data are available. Therefore, PP1 is not applied.
PP2
PP2 (Supporting)
According to VCEP guidelines, the rule for PP2 is: 'Supporting: Missense constraint computed in ExAC/gnomAD z-score > 3.09.' PIK3CA has a missense Z-score > 3.09 in gnomAD, indicating constraint. Therefore, PP2 is applied at Supporting strength because the gene is highly missense constrained and the variant is missense.
PP3
PP3 (Not Applied)
Strength Modified
According to VCEP guidelines, BP4/PP3 splicing criteria apply only to synonymous/intronic/UTR variants. For missense variants computational predictions are handled by PP3. Here, in silico tools are inconclusive. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: 'PP4: Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.' No detailed phenotype data are provided. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: 'PP5: Reputable source reports variant as pathogenic without available evidence.' The variant is not in ClinVar. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BA1 is: 'Stand Alone: Allele frequency > 0.0926%.' The allele frequency is 0%. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BS1 is: 'Strong: Allele frequency > 0.0185%.' The allele frequency is 0%. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BS2 is: 'Strong: Observed in ≥3 healthy well-phenotyped individuals.' No observations in healthy individuals are reported. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BS3 is: 'Strong/Supporting: Well validated functional studies show no damaging effect.' Available functional data are conflicting. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: 'BS4: Lack of segregation in affected members of a family.' No segregation data are available. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: 'BP1: Missense variant in a gene for which only truncating variants cause disease.' PIK3CA disease mechanism is gain-of-function. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: 'BP2: Observed in trans with a pathogenic variant in dominant disorders or in cis with another pathogenic variant.' No such data are available. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: 'BP3: In-frame indels in repetitive region without known function.' This is a missense variant. Therefore, BP3 is not applied.
BP4
BP4 (Not Applied)
Strength Modified
According to VCEP guidelines, BP4 applies only to synonymous, intronic (non-canonical), or UTR variants when splicing tools predict no impact. As this is a missense variant, BP4 is not applicable. Therefore, BP4 is not applied.
BP5
BP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: 'BP5: Variant found in a case with an alternate molecular basis for disease.' No such cases are reported. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: 'BP6: Reputable source reports variant as benign without evidence.' The variant is not in such sources. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied)
Strength Modified
According to VCEP guidelines, BP7 applies only to synonymous, intronic (non-canonical), or UTR variants with low conservation. This variant is missense, so BP7 is not applied.