PIK3CA c.2727C>G, p.Phe909Leu
NM_006218.4:c.2727C>G
COSMIC ID: COSM5624544
Variant of Uncertain Significance (VUS)
F909L in PIK3CA is a novel missense variant absent from population databases but without functional, segregation, hotspot, or clinical case evidence. Only PM2 (Supporting) is met under VCEP guidelines; classification remains Variant of Uncertain Significance.
ACMG/AMP Criteria Applied
PM2
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.2727C>G
Protein Change
F909L
Location
Exon 19
(Exon 19 of 21)
5'Exon Structure (21 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 909 in gene PIK3CA
Alternate Identifiers
COSM5624544
Variant interpretation based on transcript NM_006218.4
Genome Browser
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HGVS InputNM_006218:c.2727C>G
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 909 in gene PIK3CA
Functional Summary
The PIK3CA F909L variant has not been functionally characterized, and its effect on protein function is currently unknown.
Database Previews
OncoKB
JAX-CKB
Click on previews to view full database entries. External databases may require institutional access.
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.632
0.632
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:
primateai: D
Benign:
CADD: 3.13polyphen_prediction: benignmetasvm: 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 variant (nonsense, frame-shift, canonical ±1/2 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 a missense change (F909L), not a null variant. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to PIK3CA VCEP guidelines, the rule for PS1 is: "Strong: same amino acid change as a previously established pathogenic variant regardless of nucleotide change." The evidence for this variant shows: no previously established pathogenic variant at amino acid F909. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to PIK3CA VCEP guidelines, the rule for PS2 is: "Moderate or Strong evidence of de novo occurrence in a patient, with criteria for high-confidence somatic mutations." The evidence for this variant shows: no data on de novo occurrence. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to PIK3CA VCEP guidelines, the rule for PS3 is: "Functional assay meets acceptability criteria set by BMVCEP (PMID:31892348) with quality metrics and controls." The evidence for this variant shows: no functional characterization data. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to PIK3CA VCEP guidelines, the rule for PS4 is: "Aggregate case data absent from controls with phenotype point scoring (≥0.5 points for Supporting up to ≥16 for Very Strong)." The evidence for this variant shows: no reported clinical cases or phenotype data. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to PIK3CA VCEP guidelines, the rule for PM1 is: "Supporting: residue affects critical functional domain as defined in Table 4." The evidence for this variant shows: F909 is not located in a known critical functional hotspot domain of PIK3CA. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to PIK3CA VCEP guidelines, the rule for PM2 is: "Supporting Absent/rare from controls in an ethnically-matched cohort population sample (≥1)." The evidence for this variant shows: allele not found in gnomAD or other population databases (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: "Detected in trans with a pathogenic variant for a recessive disorder." The evidence for this variant shows: PIK3CA‐related disorders are not inherited in a recessive manner and no trans 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-repetitive regions." The evidence for this variant shows: it is a missense substitution without length change. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to PIK3CA VCEP guidelines, the rule for PM5 is: "Moderate: novel missense change at an amino acid residue where a different missense change is pathogenic." The evidence for this variant shows: no pathogenic variants reported at residue F909. 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. 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 PIK3CA VCEP guidelines, the rule for PP2 is: "Supporting: missense constraint computed in ExAC/gnomAD z-score >3.09." The evidence for this variant shows: gene‐level constraint z-score data not provided. 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 predictions are mixed (REVEL 0.63, CADD benign, SpliceAI no splice 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 disease with a single genetic etiology." The evidence for this variant shows: no phenotype data 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 variant as pathogenic without available evidence." The evidence for this variant shows: not reported in ClinVar or other expert sources. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to PIK3CA VCEP guidelines, the rule for BA1 is: "Stand Alone: allele frequency >0.0926%." The evidence for this variant shows: MAF=0% in population databases. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to PIK3CA VCEP guidelines, the rule for BS1 is: "Strong: 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 PIK3CA VCEP guidelines, the rule for BS2 is: "Strong: ≥3 homozygotes or heterozygotes in well‐phenotyped individuals." The evidence for this variant shows: no homozygotes or well‐phenotyped observations. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to PIK3CA VCEP guidelines, the rule for BS3 is: "Strong or Supporting functional studies show no damaging effect." The evidence for this variant shows: no functional assay data. 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. 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 disease mechanism is gain-of-function, not solely truncating. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to PIK3CA VCEP guidelines, the rule for BP2 is: "Supporting: variant observed in cis/trans with a known pathogenic variant." The evidence for this variant shows: no data on cis/trans 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 repetitive regions without known function." The evidence for this variant shows: it is a missense substitution. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to PIK3CA VCEP guidelines, the rule for BP4 is: "Supporting for synonymous/intronic/UTR variants when ≥2 splicing tools predict no impact." The evidence for this variant shows: it is a missense change, not eligible for BP4 under VCEP. 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 alternate 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 without evidence." The evidence for this variant shows: no such reports. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to PIK3CA VCEP guidelines, the rule for BP7 is: "Supporting for synonymous/intronic/UTR variants with low conservation." The evidence for this variant shows: it is a missense substitution. Therefore, this criterion is not applied.