PIK3CA c.301_304delinsT, p.Val101_Ile102delinsPhe
NM_006218.4:c.301_304delinsT
Likely Pathogenic
This variant is classified as Likely Pathogenic based on one Strong functional criterion (PS3), one Moderate in‐frame indel criterion (PM4), and one Supporting population criterion (PM2), consistent with VCEP and ACMG guidelines.
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.301_304delinsT
Protein Change
V101_I102delinsF
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.301_304delinsT
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
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
Functional Summary
The PIK3CA V101_I102delinsF variant has been functionally characterized as likely oncogenic, indicating a damaging 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‐insertion, not predicted to cause loss of function. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: "Strong: same amino acid change as previously established pathogenic variant by a different nucleotide change." The evidence for this variant shows: it results in a novel in‐frame delins (V101_I102delinsF), not identical to any known pathogenic amino acid substitution. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2_Strong is: "Award PS2_Strong if Criteria 1 AND Criteria 2 are fulfilled: de novo in germline with confirmed maternity/paternity and mosaic distribution across tissues." The evidence for this variant shows: no de novo or parental testing data are 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 functional studies have characterized PIK3CA V101_I102delinsF as likely oncogenic, meeting the required quality metrics. Therefore, this criterion is applied at Strong strength because a validated functional assay demonstrates a damaging effect.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: "Points assigned for phenotype according to Table 2A; strength determined by total points (e.g., ≥16 points for PS4_VeryStrong)." The evidence for this variant shows: no case‐level phenotype data or point totals are available. 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: V101_I102 is not located in a known critical PIK3CA functional domain or hotspot. Therefore, this criterion is not applied.
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 (≥1)." The evidence for this variant shows: it is not found in gnomAD, 1000G, ESP or ExAC. Therefore, this criterion is applied at Supporting strength because the variant is absent from population controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "Detected in trans with a pathogenic variant for a recessive disorder." The evidence for this variant shows: PIK3CA‐related disease is not recessive and no 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‐repeat region." The evidence for this variant shows: it causes an in‐frame deletion‐insertion replacing two amino acids with one phenylalanine in a non‐repetitive region. Therefore, this criterion is applied at Moderate strength because it results in a protein length change outside of a repetitive context.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: "Moderate: novel missense change at a codon where a different pathogenic missense change has been observed." The evidence for this variant shows: it is an in‐frame indel, not a novel missense. 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/maternity." The evidence for this variant shows: 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: "Cosegregation with disease in multiple affected family members." The evidence for this variant shows: no family segregation data are provided. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP2 is: "Missense constraint (ExAC/gnomAD z-score >3.09) for MTOR, PIK3CA, AKT3 applies to missense variants." The evidence for this variant shows: it is an in‐frame indel, 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 lines of computational evidence support a deleterious effect." The evidence for this variant shows: in silico tools (SpliceAI ≤0.07, conservation) 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 single gene disorder." The evidence for this variant shows: 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 (e.g., ClinVar) reports the variant as pathogenic." The evidence for this variant shows: it is not found in ClinVar. 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." The evidence for this variant shows: allele frequency is 0%. 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 general population." The evidence for this variant shows: allele frequency is 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: "Functional studies show no damaging effect." The evidence for this variant shows: functional studies demonstrate a damaging (oncogenic) 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 family members." The evidence for this variant shows: no segregation data are available. 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 where only truncating variants cause disease." The evidence for this variant shows: PIK3CA pathogenic variants are often activating missense/indels. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP2 is: "Observed in cis or trans with a known pathogenic variant in the same gene." 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." The evidence for this variant shows: it is not located in a repetitive region. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: "For synonymous, intronic (non‐canonical) and UTR variants, two of three splicing tools predict no impact." The evidence for this variant shows: it is an in‐frame indel. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP5 is: "Variant found in individual with an alternate molecular cause of disease." The evidence for this variant shows: no alternate molecular cause is 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 (e.g., ClinVar) reports the variant as benign." The evidence for this variant shows: it is not reported in ClinVar. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Synonymous or intronic (non‐canonical) variant with PhyloP <0.1." The evidence for this variant shows: it is an in‐frame indel. Therefore, this criterion is not applied.