PIK3CA c.1616C>G, p.Pro539Arg
NM_006218.4:c.1616C>G
COSMIC ID: COSM446010
Pathogenic
The variant PIK3CA c.1616C>G (p.P539R) is classified as Likely Pathogenic based on strong functional evidence (PS3) and multiple supporting criteria (PM1, PM2, PP3, PP5).
ACMG/AMP Criteria Applied
PS3
PM1
PM2
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.1616C>G
Protein Change
P539R
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 539 in gene PIK3CA
Alternate Identifiers
COSM446010
Variant interpretation based on transcript NM_006218.4
Genome Browser
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HGVS InputNM_006218:c.1616C>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
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).
COSMIC ID
COSM446010
Recurrence
38 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
6
Reported mutations in this domain
050100+
Domain Summary
This variant is located in a mutational hotspot or critical domain (6 mutations).
PM1 criterion applied.
Related Variants in This Domain
No evidence of other pathogenic variants at position 539 in gene PIK3CA
Functional Summary
Gain-of-Function
The PIK3CA P539R variant has been functionally characterized as a gain-of-function mutation. It is located in the helical domain of the PIK3CA protein and has been shown to be oncogenic. Functional studies demonstrate that this variant increases the stability of the PIK3CA protein and leads to constitutive phosphorylation of downstream targets such as Akt and S6. It is transforming in cell culture, as evidenced by increased downstream pathway activation, enhanced colony formation in soft agar, and growth factor-independent proliferation. Additionally, the mutation shows sensitivity to rapamycin, as indicated by decreased focus formation upon treatment.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
REVEL Score
0.893
0.893
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
Yes
Additional Predictors
Pathogenic:
polyphen_prediction: probably_damagingmutationtaster: Dmetasvm: Dmetalr: Dprimateai: D
Benign:
CADD: 5.31
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, 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 a missense change (p.P539R) in PIK3CA. Therefore, this criterion is not applied because missense variants do not meet the definition of a null variant.
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: p.P539R has not been previously reported as the same amino acid change in a pathogenic context. Therefore, this criterion is not applied because there is no identical amino acid substitution known to be pathogenic.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." The evidence for this variant shows: no data on de novo occurrence. Therefore, this criterion is not applied due to lack of de novo evidence.
PS3
PS3 (Strong)
According to VCEP guidelines, the rule for PS3 is: "Follow recommendations set forth by the SVI in conjunction with specifications added by the BMVCEP for quality metrics and minimum validation controls required (PMID: 31892348). 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 demonstrate that p.P539R is a gain‐of‐function mutation in the helical domain, increases protein stability, constitutive downstream phosphorylation, transforming activity in cell culture, and sensitivity to rapamycin. Therefore, this criterion is applied at Strong strength because the assays meet the VCEP‐specified validation criteria and show a damaging effect.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: "Assign points for phenotype evidence according to Table 2A/B when variant is absent/rare in controls (PM2)." The evidence for this variant shows: no case‐level phenotype data or published points. Therefore, this criterion is not applied due to absence of case‐level phenotypic evidence.
PM1
PM1 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM1 is: "Supporting: Residues affecting critical functional domains provided in Table 4 for each gene." The evidence for this variant shows: p.P539R is located in the helical domain of PIK3CA, a known mutational hotspot with critical function. Therefore, this criterion is applied at Supporting strength because the variant lies in a well‐established critical domain.
PM2
PM2 (Supporting) Strength Modified
According to 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: absent from gnomAD and other population databases (MAF=0%). Therefore, this criterion is applied at Supporting strength because the variant is not observed in 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: no data on trans occurrence with another pathogenic allele. Therefore, this criterion is not applied due to lack of evidence for trans occurrence.
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 a non‐repeat region or stop‐loss." The evidence for this variant shows: it is a missense substitution without change in protein length. Therefore, this criterion is not applied because the variant does not alter protein length.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different missense change is pathogenic." The evidence for this variant shows: no other pathogenic missense at residue Pro539 has been reported. Therefore, this criterion is not applied due to absence of other pathogenic changes at the same residue.
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. Therefore, this criterion is not applied due to lack of de novo evidence.
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 due to absence of segregation evidence.
PP2
PP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP2 is: "Supporting: Missense constraint computed in ExAC/gnomAD z‐score >3.09 (applicable to PIK3CA)." The evidence for this variant shows: no gene‐level constraint z‐score provided. Therefore, this criterion is not applied due to missing constraint score 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: REVEL score 0.89 (>0.75 threshold), plus damaging predictions from PolyPhen‐2, MutationTaster, MetaSVM, MetaLR, and PrimateAI. Therefore, this criterion is applied at Supporting strength because multiple in silico tools predict a deleterious effect.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Patient’s phenotype or family history highly specific for a disease with a single genetic etiology." The evidence for this variant shows: no patient phenotype data provided. Therefore, this criterion is not applied due to lack of phenotype information.
PP5
PP5 (Supporting)
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: ClinVar entry by one clinical laboratory classifies p.P539R as Likely Pathogenic without accessible primary evidence. Therefore, this criterion is applied at Supporting strength because a reputable database reports pathogenicity without available underlying data.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Stand‐alone: Allele frequency >0.0926%." The evidence for this variant shows: absent from population databases (MAF=0%). Therefore, this criterion is not applied because the allele frequency is well below the BA1 threshold.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Strong: Allele frequency >0.0185%." The evidence for this variant shows: absent from gnomAD (MAF=0%). Therefore, this criterion is not applied because the allele frequency is below the BS1 threshold.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Strong: ≥3 homozygotes in gnomAD or ≥3 heterozygotes in well‐phenotyped family members." The evidence for this variant shows: no homozygotes in gnomAD and no family data. Therefore, this criterion is not applied due to absence of sufficient observations.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: "Strong: Well‐established functional studies show no damaging effect." The evidence for this variant shows: functional studies demonstrate damaging gain‐of‐function. Therefore, this criterion is not applied because studies support pathogenicity, not benign effect.
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 due to absence of segregation information.
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 cause disease." The evidence for this variant shows: PIK3CA disease mechanism involves gain‐of‐function missense variants. Therefore, this criterion is not applied because missense is a known mechanism for PIK3CA pathogenesis.
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 fully penetrant dominant gene." The evidence for this variant shows: no data on cis/trans observations. Therefore, this criterion is not applied due to lack of companion variant data.
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 single amino acid substitution. Therefore, this criterion is not applied because it does not involve an in‐frame indel.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: "Supporting for synonymous/intronic variants if two of three splicing tools predict no impact." The evidence for this variant shows: missense substitution, not applicable to 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 data. Therefore, this criterion is not applied due to absence of alternate molecular findings.
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 benign reports. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Supporting for synonymous/intronic variants with low conservation (PhyloP<0.1)." The evidence for this variant shows: missense substitution, not applicable to synonymous/intronic classification. Therefore, this criterion is not applied.