PIK3CA c.1625A>T, p.Glu542Val
NM_006218.4:c.1625A>T
COSMIC ID: COSM1041493
Likely Pathogenic
The PIK3CA E542V variant is classified as Likely Pathogenic based on a strong functional assay (PS3) per VCEP, moderate evidence from PM5 for a novel missense change at a codon with known pathogenic variation, and supporting evidence from PM1 (hotspot domain), PM2 (absent from controls), and PP2 (gene‐specific missense constraint).
ACMG/AMP Criteria Applied
PS3
PM1
PM2
PM5
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.1625A>T
Protein Change
E542V
Location
Exon 10
(Exon 10 of 21)
5'Exon Structure (21 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 542 in gene PIK3CA
Alternate Identifiers
COSM1041493
Variant interpretation based on transcript NM_006218.4
Genome Browser
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HGVS InputNM_006218:c.1625A>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 248294Alt: 0Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0%, 0/248294 alleles, homozygotes = 0) but does not appear at a higher frequency in any of the selected populations. The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Unknown
Publications (0)
No publication details.
Clinical Statement
COSMIC ID
COSM1041493
Recurrence
24 occurrences
PM1 Criteria
Applied
Criterion PM1 is applied based on the high recurrence in COSMIC database.
COSMIC Database Preview
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Functional Impact
Functional Domain
Hotspot Status
Hotspot
PM1
Mutation Count
1860
Reported mutations in this domain
050100+
Domain Summary
This variant is located in a mutational hotspot or critical domain (1860 mutations).
PM1 criterion applied.
Related Variants in This Domain
No evidence of other pathogenic variants at position 542 in gene PIK3CA
Functional Summary
The PIK3CA E542V variant has been functionally characterized as oncogenic. It is located in the helical domain of the protein and confers a gain of function. Experimental evidence demonstrates that this mutation leads to increased downstream pathway activation, including enhanced phosphorylation of Akt and Mek1/2, and supports growth-factor independent cell survival. It is also transforming in cell culture models.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
REVEL Score
0.665
0.665
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_damagingprimateai: D
Benign:
CADD: 5.34metasvm: Tmetalr: T
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 variants (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: NM_006218.4:c.1625A>T is a missense change, not predicted to cause loss of function. 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: E542V is a distinct amino acid change from the known pathogenic E542K. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: Strong if de novo with confirmed maternity/paternity and tissue evidence; Moderate if partially fulfilled. The evidence for this variant shows: no de novo or parental testing data available. 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: well‐established in vitro studies demonstrate gain‐of‐function in the helical domain with increased Akt/Mek1/2 phosphorylation and transforming activity. Therefore, this criterion is applied at Strong strength because the functional assays meet VCEP quality metrics supporting a damaging effect.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: points‐based case evidence only if variant meets PM2, with thresholds for Supporting, Moderate, Strong, Very Strong. The evidence for this variant shows: no published case series or phenotype scoring available. Therefore, this criterion is not applied.
PM1
PM1 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM1 is: Residues affecting critical functional domains provided in Table 4 for each gene (Supporting strength). The evidence for this variant shows: E542 is in the well‐established helical domain mutational hotspot of PIK3CA. Therefore, this criterion is applied at Supporting strength because it lies in a critical functional domain without benign variation.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: Absent/rare from controls in an ethnically‐matched cohort population sample (Supporting strength). The evidence for this variant shows: not found in gnomAD (MAF 0%). Therefore, this criterion is applied at Supporting strength because it is absent from population controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: for recessive disorders, detection in trans with a pathogenic variant. The evidence for this variant shows: PIK3CA E542V is not studied in a recessive context and no trans data. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: protein length changes due to in‐frame indels or stop‐loss. The evidence for this variant shows: E542V is a missense change without protein length alteration. Therefore, this criterion is not applied.
PM5
PM5 (Moderate)
According to standard ACMG guidelines, the rule for PM5 is: novel missense change at an amino acid residue where a different pathogenic missense change has been observed (Moderate strength). The evidence for this variant shows: E542K is a well‐established pathogenic variant at the same residue. Therefore, this criterion is applied at Moderate strength because this is a novel change at a codon with known pathogenic variation.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: assumed de novo without confirmation. The evidence for this variant shows: no de novo data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: cosegregation with disease in multiple affected family members. The evidence for this variant shows: no family segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Supporting)
According to VCEP guidelines, the rule for PP2 is: missense constraint computed in ExAC/gnomAD with z‐score >3.09 applicable to PIK3CA (Supporting strength). The evidence for this variant shows: PIK3CA exhibits high missense constraint (z‐score >3.09). 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. The evidence for this variant shows: mixed in silico predictions (some tools benign, some pathogenic). 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 clinical phenotype or family history 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 the variant as pathogenic without available evidence. The evidence for this variant shows: not present in ClinVar or other databases. 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% in general population (Stand‐alone). The evidence for this variant shows: MAF 0% in gnomAD. 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% in population (Strong). The evidence for this variant shows: MAF 0% in gnomAD. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: ≥3 homozygotes or well‐phenotyped heterozygotes in population (Strong). The evidence for this variant shows: no homozygotes or reported heterozygotes. 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 (Strong/Supporting). The evidence for this variant shows: functional studies show a damaging gain‐of‐function 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 gene where only truncating variants cause disease. The evidence for this variant shows: PIK3CA is an oncogene driven by missense gain‐of‐function. 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 recessive disorder. The evidence for this variant shows: no trans data or recessive context. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: in‐frame indels in repetitive regions without functional impact. The evidence for this variant shows: missense, not an indel. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: applicable only to synonymous, intronic (except canonical splice sites), or UTR variants if splicing tools predict no impact. The evidence for this variant shows: missense 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 alternate molecular basis for disease. The evidence for this variant shows: no such data. 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 without evidence. The evidence for this variant shows: no database entries. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: synonymous or intronic variants with low conservation. The evidence for this variant shows: missense variant. Therefore, this criterion is not applied.