PIK3CA c.2779G>T, p.Gly927Ter
NM_006218.4:c.2779G>T
Likely Pathogenic
The p.G927* variant in PIK3CA is a truncating change in a gene where gain-of-function causes disease; loss-of-function is not established. It is absent from population databases (PM2 supporting) but lacks additional evidence. Therefore, the variant is classified as VUS.
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.2779G>T
Protein Change
G927*
Location
Exon 19
(Exon 19 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.2779G>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
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP 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: p.G927* is a null variant but PIK3CA disease mechanism is gain-of-function rather than loss-of-function. Therefore, this criterion is not applied because LOF is not an established mechanism for PIK3CA-related disease.
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: no known pathogenic variant results in p.G927*. Therefore, this criterion is not applied because there is no prior pathogenic variant at this codon.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2_Strong is: "De novo occurrence with confirmed maternity and paternity and allelic fraction criteria in tissue samples". The evidence for this variant shows: no de novo or parental data available. Therefore, this criterion is not applied due to lack of de novo confirmation.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS3 is: "Well-validated functional studies showing a damaging effect on the gene or gene product". The evidence for this variant shows: no functional studies have been performed. Therefore, this criterion is not applied due to absence of functional data.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: "Case reports with phenotypic specificity and points-based system for variants absent from controls". The evidence for this variant shows: no reported cases in the literature. Therefore, this criterion is not applied due to lack of case data.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1_Supporting is: "Residues affecting critical functional domains provided in gene-specific table". The evidence for this variant shows: codon 927 is not listed as a critical functional domain in PIK3CA. 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: absent from gnomAD and other population databases. Therefore, this criterion is applied at Supporting strength because the variant is absent from controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "Detected in trans with a pathogenic variant in recessive disorders". The evidence for this variant shows: PIK3CA-related disorders are not recessive and no trans data is available. 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 not at repeat regions". The evidence for this variant shows: this is a nonsense variant causing truncation, not an in-frame indel. Therefore, this criterion is not applied.
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: this is a nonsense variant, not 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, but without confirmation of maternity/paternity". The evidence for this variant shows: no parental or 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 available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP2 is: "Missense constraint z-score >3.09 in gnomAD for MTOR and PIK3CA". The evidence for this variant shows: this is a nonsense variant, not 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: computational tools yield mixed or benign predictions and the VCEP does not apply PP3 to truncating variants. 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 clinical 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". The evidence for this variant shows: not present in ClinVar or other reputable databases. 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 controls". The evidence for this variant shows: absent from controls. 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 controls". The evidence for this variant shows: absent from controls. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Observed in ≥3 unrelated homozygotes or well-phenotyped heterozygotes". 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: "Well-validated functional studies show no damaging effect". The evidence for this variant shows: no functional 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 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 a gene where only LOF causes disease". The evidence for this variant shows: this is a nonsense variant, not missense. 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 for a dominant disorder or in cis with a pathogenic variant". 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 indels in repetitive regions without functional impact". The evidence for this variant shows: this is a nonsense variant. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: "Synonymous or noncoding variants with no predicted splicing impact". The evidence for this variant shows: this is a nonsense variant. 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 context. 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". The evidence for this variant shows: not present in such sources. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Synonymous or intronic variants at non-conserved sites". The evidence for this variant shows: this is a nonsense variant. Therefore, this criterion is not applied.