PIK3CA c.330_335del, p.Glu110_Ile112delinsAsp
NM_006218.4:c.330_335del
Likely Pathogenic
This variant exhibits strong functional evidence of oncogenic activation (PS3), along with supportive absence from controls (PM2), location in a critical domain (PM1), and an in‐frame protein length change (PM4). The combination of one strong, one moderate, and two supporting criteria yields a Likely Pathogenic classification.
ACMG/AMP Criteria Applied
PS3
PM1
PM2
PM4
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.330_335del
Protein Change
E110_I112delinsD
Location
Exon 2
(Exon 2 of 21)
5'Exon Structure (21 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_006218.4
Genome Browser
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HGVS InputNM_006218:c.330_335del
Active Tracks
ConservationRefSeqClinVargnomAD
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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
182
Reported mutations in this domain
050100+
Domain Summary
This variant is located in a mutational hotspot or critical domain (182 mutations).
PM1 criterion applied.
Related Variants in This Domain
Functional Summary
The PIK3CA E110_I112delinsD variant has been functionally characterized and shown to be activating. Expression of this mutation in Ba/F3 and MCF10A cell lines results in increased proliferation in the absence of growth factors, indicating a likely oncogenic effect.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
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." The evidence for this variant shows it is an in‐frame deletion‐insertion, not a null variant. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change." No such same amino acid change has been reported. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." There are no de novo data. Therefore, this criterion is not applied.
PS3
PS3 (Strong)
According to VCEP guidelines, the rule for PS3 is: "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 that expression of E110_I112delinsD in Ba/F3 and MCF10A cell lines results in increased proliferation in the absence of growth factors, indicating an activating oncogenic effect. Therefore, this criterion is applied at Strong strength because a well‐validated in vitro assay demonstrates a damaging (activating) effect on the gene product.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, PS4 requires case‐level phenotype data with point scoring and PM2 to be met. No case reports or phenotypic scoring have been provided. Therefore, this criterion is not applied.
PM1
PM1 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM1 is: "Supporting: Residues affecting critical functional domains provided in Table 4 for each gene." The evidence for this variant shows it lies within the adaptor‐binding (ABD) domain of PIK3CA, a critical functional region. Therefore, this criterion is applied at Supporting strength.
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." The evidence for this variant shows it is absent from gnomAD and other population databases. Therefore, this criterion is applied at Supporting strength.
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." No recessive trans data are available. Therefore, this criterion is not applied.
PM4
PM4 (Moderate)
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in‐frame deletions/insertions in a non‐repetitive region." The evidence for this variant shows an in‐frame deletion‐insertion of three amino acids in a non‐repetitive region. Therefore, this criterion is applied at Moderate strength.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different missense change is pathogenic." This variant is not a simple missense and no such comparison exists. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, without confirmation of paternity and maternity." No de novo data are available. Therefore, this criterion is not applied.
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." No segregation data are provided. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to VCEP guidelines, PP2 applies to missense variants in a gene with low benign missense rate. This variant is an in‐frame deletion‐insertion, not a missense. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP3 is: "Multiple computational tools support a deleterious effect." In silico tools (SpliceAI, etc.) predict no impact. Therefore, this criterion is not applied.
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." No phenotype data are provided. Therefore, this criterion is not applied.
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." No such reports exist. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 requires an allele frequency >0.0926%. The variant is absent in population databases. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 requires an allele frequency >0.0185%. The variant is absent in population databases. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 requires ≥3 homozygotes or heterozygotes in well‐phenotyped individuals. No such observations exist. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, BS3 requires well‐established functional studies showing no damaging effect. Functional data show a damaging (activating) effect. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS4 requires lack of segregation in affected members or presence in unaffected. No such data are provided. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP1 applies to missense variants in genes where only truncating variants cause disease. Not applicable here. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 applies when a variant is observed in cis or trans with a known pathogenic variant. No such data exist. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 applies to in‐frame indels in repetitive regions without predicted functional impact. This region is not repetitive. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, BP4 is only applicable to synonymous or intronic variants with splicing predictions. This is an in‐frame deletion. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP5 applies when a variant is found in a case with an alternate molecular basis. No such context exists here. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 applies when a variant is reported as benign by a qualified source without evidence. No such report is available. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, BP7 applies only to synonymous variants at non‐conserved sites. This is an in‐frame deletion. Therefore, this criterion is not applied.