PIK3CA c.3074C>A, p.Thr1025Asn
NM_006218.4:c.3074C>A
COSMIC ID: COSM772
Pathogenic
The PIK3CA T1025N variant demonstrates strong functional evidence (PS3), moderate evidence for other pathogenic missense variants at the same residue (PM5), and supporting evidence for hotspot location (PM1), absence from controls (PM2), computational deleteriousness (PP3), and a reputable pathogenic report (PP5). These criteria collectively support a Pathogenic classification.
ACMG/AMP Criteria Applied
PS3
PM1
PM2
PM5
PP3
PP5
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.3074C>A
Protein Change
T1025N
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 1025: T1025A, T1025S
Alternate Identifiers
COSM772
Variant interpretation based on transcript NM_006218.4
Genome Browser
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HGVS InputNM_006218:c.3074C>A
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
Likely Pathogenic
Based on 1 submitter review in ClinVar
Submitter Breakdown
1 LP
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Likely pathogenic (1 clinical laboratories).
Functional Impact
Functional Domain
Hotspot Status
Hotspot
PM1
Mutation Count
16
Reported mutations in this domain
050100+
Domain Summary
This variant is located in a mutational hotspot or critical domain (16 mutations).
PM1 criterion applied.
Related Variants in This Domain
ClinVar reports other pathogenic variants at position 1025: T1025A, T1025S
PM5 criterion applied.
Functional Summary
Gain-of-Function
The PIK3CA T1025N variant has been functionally characterized as a gain-of-function mutation. Experimental evidence demonstrates that this variant increases proliferation in Ba/F3 and MCF10A cell lines in the absence of growth factors, indicating an activating effect. Additionally, it enhances transformation ability in cell culture, supporting its role as an oncogenic mutation.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
REVEL Score
0.439
0.439
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Pathogenic
PP3 Applied
No
Additional Predictors
Pathogenic:
sift: Dmutationtaster: Dprovean: Dmetasvm: Dmetalr: Dprimateai: Ddeogen2: D
Benign:
CADD: 5.24mutationassessor: Lfathmm: 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, PVS1 is: 'Null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where loss of function is a known mechanism of disease.' The evidence for this variant shows: it is a missense change (T1025N), not a null variant. Therefore, this criterion is not applied because the variant type does not meet PVS1 requirements.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, PS1 (strong) is: 'Same amino acid change as a previously established pathogenic variant but by a different nucleotide change.' The evidence for this variant shows: no other pathogenic variant at codon 1025 resulting in T1025 has been reported by a different nucleotide change. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, PS2_Strong/PS2_Moderate pertain to confirmed de novo somatic variants with parental or allele-fraction data. The evidence for this variant shows: no parental testing or allele fraction comparisons are available. Therefore, PS2 is not applied.
PS3
PS3 (Strong)
According to VCEP guidelines, PS3_Strong is: 'Award PS3 if the functional assay meets the acceptability criteria set forth by the VCEP (PMID: 31892348) with specified quality metrics.' The evidence for this variant shows: in vitro assays in Ba/F3 and MCF10A cell lines demonstrate gain-of-function, increased proliferation without growth factors, and enhanced transformation. Therefore, PS3 is applied at Strong strength because these well-controlled functional studies meet VCEP standards.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, PS4 requires case-level phenotype data and points assignment for absent/rare variants. The evidence for this variant shows: no case-level phenotypic series with point scoring is provided. Therefore, PS4 is not applied.
PM1
PM1 (Supporting) Strength Modified
According to VCEP guidelines, PM1_Supporting is: 'Residues affecting critical functional domains provided in Table 4 for each gene.' The evidence for this variant shows: T1025 lies in the kinase domain mutational hotspot region of PIK3CA. Therefore, PM1 is applied at Supporting strength because it is in a well-established functional domain.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, PM2_Supporting is: 'Absent/rare from controls in an ethnically matched cohort population sample.' The evidence for this variant shows: it is not present in gnomAD or other population databases. Therefore, PM2 is applied at Supporting strength because it is absent from controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM3 applies to recessive disorders when detected in trans with a pathogenic variant. The evidence for this variant shows: PIK3CA-related conditions are dominant and no trans observation is relevant. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM4 applies to in-frame indels or stop-loss variants altering protein length. The evidence for this variant shows: it is a missense change without length alteration. Therefore, PM4 is not applied.
PM5
PM5 (Moderate)
According to VCEP guidelines, PM5_Moderate is: '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 missense substitutions have been reported at codon 1025. Therefore, PM5 is applied at Moderate strength.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM6 applies to assumed de novo variants without confirmation of paternity/maternity. The evidence for this variant shows: no de novo assessment is available. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP1 applies to cosegregation with disease in multiple affected family members. The evidence for this variant shows: no familial segregation data are available. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to VCEP guidelines, PP2_Supporting is: 'Missense constraint computed in ExAC/gnomAD; award PP2 if z-score >3.09.' The evidence for this variant shows: no PIK3CA missense constraint z-score was provided. Therefore, PP2 is not applied due to lack of necessary constraint data.
PP3
PP3 (Supporting)
According to standard ACMG guidelines, PP3 is: 'Multiple lines of computational evidence support a deleterious effect.' The evidence for this variant shows: in silico predictors (SIFT, MutationTaster, MetaSVM, etc.) are predominantly deleterious. Therefore, PP3 is applied at Supporting strength.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP4 applies to highly specific patient phenotype or family history. The evidence for this variant shows: no specific phenotype data linking T1025N to a PIK3CA-related syndrome. Therefore, PP4 is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, PP5 is: 'Reputable source reports variant as pathogenic, but evidence not available for independent evaluation.' The evidence for this variant shows: ClinVar reports it as Likely pathogenic (1 laboratory). Therefore, PP5 is applied at Supporting strength.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BA1 is: 'Allele frequency is greater than 5% in control populations.' The evidence for this variant shows: allele frequency is 0%. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS1 is: 'Allele frequency is greater than expected for disorder.' The evidence for this variant shows: allele frequency is 0%. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS2 is: 'Observed in healthy adult individuals for a recessive (≥3 homozygotes) or dominant (≥3 heterozygotes) condition.' The evidence for this variant shows: no such observations. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS3 is: 'Well-established functional studies show no damaging effect.' The evidence for this variant shows: functional studies demonstrate gain-of-function. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS4 is: 'Lack of segregation in affected members of a family.' The evidence for this variant shows: no segregation data. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP1 is: 'Missense variant in a gene for which primarily truncating variants cause disease.' The evidence for this variant shows: PIK3CA disease mechanism is gain-of-function from missense variants. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 is: 'Observed in trans with a pathogenic variant for a fully penetrant dominant gene or in cis with a pathogenic variant.' The evidence for this variant shows: no such observations. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 is: 'In-frame indels in repetitive region without a known function.' The evidence for this variant shows: it is a single amino acid substitution, not an indel. Therefore, BP3 is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP4 is: 'Multiple lines of computational evidence suggest no impact on gene or gene product.' The evidence for this variant shows: conflicting and predominantly deleterious predictions. Therefore, BP4 is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP5 is: 'Variant found in a case with an alternate molecular basis for disease.' The evidence for this variant shows: no alternate molecular cause reported. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 is: 'Reputable source reports variant as benign.' The evidence for this variant shows: ClinVar reports likely pathogenic, not benign. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP7 is: 'Synonymous variant with no predicted splicing impact and low conservation.' The evidence for this variant shows: it is nonsynonymous. Therefore, BP7 is not applied.