PIK3CA c.3001C>T, p.Leu1001Phe
NM_006218.4:c.3001C>T
COSMIC ID: COSM6438093
Variant of Uncertain Significance (VUS)
NM_006218.4:c.3001C>T (PIK3CA p.L1001F) remains classified as a Variant of Uncertain Significance based on only PM2_Supporting (absent from population controls) and PP3_Supporting (deleterious computational predictions) without additional moderate or strong evidence.
ACMG/AMP Criteria Applied
PM2
PP2
PP3
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.3001C>T
Protein Change
L1001F
Location
Exon 21
(Exon 21 of 21)
5'Exon Structure (21 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 1001 in gene PIK3CA
Alternate Identifiers
COSM6438093
Variant interpretation based on transcript NM_006218.4
Genome Browser
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HGVS InputNM_006218:c.3001C>T
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
No evidence of other pathogenic variants at position 1001 in gene PIK3CA
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.718
0.718
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: Dpolyphen_prediction: probably_damagingmutationtaster: Dprovean: Dmetasvm: Dmetalr: Dprimateai: Ddeogen2: D
Benign:
CADD: 5.53fathmm: 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 Variant (nonsense, fs, start codon, splicing +1/2, startgain, single or multi-exon deletion) in a gene where LOF is a known mechanism of disease'. The evidence for this variant shows: NM_006218.4:c.3001C>T is a missense change (L1001F). Therefore, this criterion is not applied because the variant type does not meet the rule.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: '**Strong Strength**: Strong No change. Modification Type: None'. The evidence for this variant shows: there is no previously established pathogenic variant resulting in the same amino acid change (L1001F). Therefore, this criterion is not applied because the amino acid change is novel.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: '**Strong Strength**: Strong Award the PS2_Strong point if Criteria 1 AND Criteria 2 are fulfilled... **Moderate Strength**: Moderate Award the PS2_Moderate point if Criteria 1 is fulfilled, OR if parents are not available but Criteria 2 is fulfilled. Modification Type: Disease-specific, Strength'. The evidence for this variant shows: no data on de novo occurrence or mosaicism in parent and affected tissues. Therefore, this criterion is not applied due to lack of de novo evidence.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS3 is: 'Strong Follow recommendations set forth by the SVI ... Award PS3 if the functional assay meets the acceptability criteria ...'. The evidence for this variant shows: no functional studies have been reported for PIK3CA L1001F. Therefore, this criterion is not applied due to absence of functional evidence.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: '**Very Strong Strength**: PS4_VeryStrong ≥ 16 points ... **Strong Strength**: PS4_Strong = 3.5-15.75 points ... (phenotype-based points). Modification Type: Disease-specific, Strength'. The evidence for this variant shows: no reported case counts or phenotype data. Therefore, this criterion is not applied due to lack of case/phenotype evidence.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: '**Supporting Strength**: Supporting Residues affecting critical functional domains provided in Table 4 for each gene. Modification Type: Strength'. The evidence for this variant shows: L1001 is not located in a critical functional domain or known hotspot region of PIK3CA. Therefore, this criterion is not applied because the variant is outside validated functional domains.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: '**Supporting Strength**: Supporting Absent/rare from controls in an ethnically-matched cohort population sample (≥1). Modification Type: Disease-specific'. The evidence for this variant shows: it is absent from gnomAD (MAF = 0%). 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: 'For recessive disorders, detected in trans with a pathogenic variant.'. The evidence for this variant shows: PIK3CA-related disease is not inherited in a recessive manner and no trans configuration data exist. 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 deletions/insertions in non-repeat regions or stop-loss variants.'. The evidence for this variant shows: it is a missense variant with no change in protein length. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: '**Moderate Strength**: Moderate No change. Modification Type: None'. The evidence for this variant shows: there is no other pathogenic missense variant reported at codon L1001. 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 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 in a gene definitively known to cause the disease.'. The evidence for this variant shows: no segregation data are available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP2 is: '**Supporting Strength**: Supporting Missense constraint computed in ExAC/gnomAD was utilized. Award PP2 if the z-score > 3.09. (applicable to MTOR, PIK3CA and AKT3 but not PIK3R2)'. The evidence for this variant shows: gene constraint z-score data are not provided. Therefore, this criterion cannot be applied due to missing constraint data.
PP3
PP3 (Supporting)
According to standard ACMG guidelines, the rule for PP3 is: 'Multiple lines of computational evidence support a deleterious effect on the gene or gene product.'. The evidence for this variant shows: multiple in silico predictors (SIFT, PolyPhen, MutationTaster, PROVEAN, MetaSVM, MetaLR, PrimateAI, DEOGEN2, REVEL=0.72) predict damaging effect. Therefore, this criterion is applied at Supporting strength because of concordant deleterious computational predictions.
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 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 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 such reports exist. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: '**Stand Alone Strength**: Stand Alone Allele frequency (>0.0926%).'. The evidence for this variant shows: allele frequency is 0% in gnomAD. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: '**Strong Strength**: Strong Allele frequency (>0.0185%).'. The evidence for this variant shows: allele frequency is 0% in gnomAD. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: '**Strong Strength**: Strong Award BS2 if ≥3 homozygotes present in gnomAD or ≥3 heterozygous in well phenotyped family members.'. The evidence for this variant shows: no homozygotes or heterozygotes reported. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: '**Strong Strength**: Strong Follow recommendations ... (functional studies).'. The evidence for this variant shows: no functional studies demonstrating benign 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: PIK3CA gain-of-function missense variants are known to cause disease, not truncating. 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 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 without a known function.'. The evidence for this variant shows: it is a missense variant, not an in-frame indel. 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 positions (except canonical splice sites) or non-coding variants in the UTRs, if two out of three of the splicing prediction tools predicted no impact.'. The evidence for this variant shows: it is a missense change, not applicable for splicing predictions. 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 cases 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 reports exist. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: 'Synonymous variant with no predicted splice impact and nucleotide is non-conserved (PhyloP <0.1).'. The evidence for this variant shows: it is a missense change, not synonymous. Therefore, this criterion is not applied.