PIK3CA c.1342_1353del, p.Val448_Gly451del
NM_006218.4:c.1342_1353del
COSMIC ID: COSM7346046
Likely Pathogenic
Likely Pathogenic based on strong functional evidence (PS3_Strong), supporting absence from controls (PM2_Supporting), and moderate evidence from protein length change (PM4_Moderate).
ACMG/AMP Criteria Applied
PS3
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.1342_1353del
Protein Change
V448_G451del
Location
Exon 8
(Exon 8 of 21)
5'Exon Structure (21 total)3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSM7346046
Variant interpretation based on transcript NM_006218.4
Genome Browser
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HGVS InputNM_006218:c.1342_1353del
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
238
Reported mutations in this domain
050100+
Domain Summary
This variant is located in a mutational hotspot or critical domain (238 mutations).
PM1 criterion applied.
Related Variants in This Domain
Functional Summary
The PIK3CA V448_G451del variant has been functionally characterized and is likely oncogenic. Experimental studies have shown that expression of this mutation in Ba/F3 and MCF10A cell lines leads to increased proliferation in the absence of growth factors, indicating an activating 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 or multi‐exon 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, not predicted to create a null allele. 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." The evidence for this variant shows V448_G451del is novel with no identical established pathogenic amino acid change. 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." The evidence for this variant shows no parental genotype data to assess de novo status. 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 Ba/F3 and MCF10A cell line assays demonstrated growth factor–independent proliferation attributable to the V448_G451del mutation. Therefore, this criterion is applied at Strong strength because the experimental studies meet VCEP quality and validation criteria for a damaging effect.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "The prevalence of the variant in affected individuals is significantly increased compared with controls." The evidence for this variant shows no case‐level or phenotypic data in affected individuals. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1_Supporting is: "Residues affecting critical functional domains provided in Table 4 for each gene." The evidence for this variant shows V448_G451 is not a recognized mutational hotspot in PIK3CA (COSMIC recurrence = 0). Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2_Supporting is: "Absent/rare from controls in an ethnically‐matched cohort population sample (≥1)." The evidence for this variant shows it is absent from gnomAD and other population databases (MAF = 0%). Therefore, this criterion is applied at Supporting strength because the variant is not observed in 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." The evidence for this variant shows it is a heterozygous somatic change with no evidence of trans configuration in a recessive context. Therefore, this criterion is not applied.
PM4
PM4 (Moderate)
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes as a result of in‐frame deletions or insertions in a non‐repeat region." The evidence for this variant shows a 12-bp in‐frame deletion deleting four amino acids (V448–G451) in PIK3CA. Therefore, this criterion is applied at Moderate strength because it results in a protein length change in a non‐repeat region.
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." The evidence for this variant shows it is an in‐frame deletion, not a missense change. 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." The evidence for this variant shows no de novo data 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." The evidence for this variant shows no segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with a low rate of benign missense variation and pathogenic missense variants are common." The evidence for this variant shows it is an in‐frame deletion, not a missense variant. Therefore, this criterion is not applied.
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." The evidence for this variant shows in silico tools do not predict a deleterious effect on splicing or protein function. 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." The evidence for this variant shows no detailed phenotype data. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "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 no ClinVar entry or other reputable classification. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Allele frequency >0.0926%." The evidence for this variant shows MAF = 0%, well below the threshold. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Allele frequency >0.0185%." The evidence for this variant shows MAF = 0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "≥3 homozygotes in gnomAD or ≥3 heterozygotes in well‐phenotyped family members." The evidence for this variant shows no such observations. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: "Well‐established functional studies show no damaging effect on protein function or splicing." The evidence for this variant shows functional studies indicate a damaging activating effect. Therefore, this criterion is not applied.
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." The evidence for this variant shows no segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene for which primarily truncating variants are known to cause disease." The evidence for this variant shows it is an in‐frame deletion in a gene where activating missense and in‐frame changes are known to be pathogenic. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for a fully penetrant dominant disorder or in cis with a pathogenic variant in any inheritance pattern." The evidence for this variant shows no such observations. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In‐frame deletions/insertions in a repetitive region without a known function." The evidence for this variant shows it is in a non‐repetitive, functional domain. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: "Award BP4 for a synonymous, intronic position or non‐coding UTR variant if two of three splicing tools predict no impact." The evidence for this variant shows it is an exonic in‐frame deletion, not a synonymous or non‐coding change. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternative molecular basis for disease." The evidence for this variant shows no alternative molecular cause reported. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign but evidence not available." The evidence for this variant shows no such reputable benign report. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Synonymous, intronic (except canonical splice sites), or UTR variants at non‐conserved nucleotides." The evidence for this variant shows it is an in‐frame deletion. Therefore, this criterion is not applied.