PIK3CA c.2782C>T, p.Gln928Ter
NM_006218.4:c.2782C>T
Likely Pathogenic
The variant NM_006218.4:c.2782C>T (p.Q928*) in PIK3CA is a truncating change in a gene with gain-of-function disease mechanism. Absent from population databases (PM2_Supporting) but lacking additional supporting evidence, 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.2782C>T
Protein Change
Q928*
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.2782C>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 standard ACMG guidelines, the rule for PVS1 is: 'Null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where loss of function is a known mechanism of disease.' The evidence for this variant shows a truncating (nonsense) change in PIK3CA, but PIK3CA is an oncogene with gain-of-function disease mechanism rather than loss-of-function. Therefore, PVS1 is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines for PS1 (no modification), the rule is: 'Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.' There is no reported pathogenic variant at codon Q928 in PIK3CA. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines for PS2, de novo occurrence with confirmed maternity and paternity or somatic allele fraction criteria are required. No de novo or tissue-specific allele data are available. Therefore, PS2 is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines for PS3, well-validated functional assays meeting specified quality metrics are required. No functional characterization of Q928* in PIK3CA has been reported. Therefore, PS3 is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines for PS4, case-level or segregation data scoring points against phenotype criteria (in absence from controls) are required. No case reports or phenotype data for this variant are available. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines for PM1, variants affecting critical functional domains as defined in disease-specific tables warrant supporting evidence. No domain information supports Q928* in a critical PIK3CA domain. Therefore, PM1 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 present in gnomAD or other population databases (MAF = 0%). Therefore, PM2 is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM3 applies to variants in trans with a pathogenic variant for recessive disorders. PIK3CA variant Q928* is not evaluated in a recessive context and no in trans data are available. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM4 applies to protein length changes due to in-frame indels or stop losses in non-repeat regions. This variant is a nonsense change triggering NMD rather than an in-frame alteration. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines for PM5 (no modification), the rule is: 'Novel missense change at an amino acid residue where a different missense change is pathogenic.' Q928* is a nonsense variant, not missense. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM6 applies to assumed de novo occurrences without confirmation. No parental data exist. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP1 requires cosegregation with disease in multiple affected family members. No segregation data are available. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to VCEP guidelines for PP2, missense constraint (z-score >3.09) supports missense variants. Q928* is not missense. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP3 applies when multiple computational predictors support a deleterious effect. As a truncating variant, computational impact predictors are not applicable. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP4 requires a highly specific phenotype for a single gene disorder. No phenotype data have been provided. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 applies when a reputable source has reported the variant as pathogenic. This variant is not found in ClinVar or other expert-curated databases. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines for BA1, allele frequency >0.0926% is stand-alone benign. The variant frequency is 0% in population databases. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines for BS1, allele frequency >0.0185% is strong benign. The variant is absent from controls. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines for BS2, observation of ≥3 homozygotes in gnomAD or well-phenotyped family members supports benign. No homozygotes or family data are present. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines for BS3, well-validated functional studies showing no damaging effect are required. No such data exist for Q928*. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS4 applies when lack of segregation in affected members is observed. No segregation evidence is available. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP1 applies for missense variants in genes where only truncating variants cause disease. Q928* is truncating. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 applies when variant is observed in cis/trans with a pathogenic variant in the same gene. No such data exist. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 applies to in-frame indels in repetitive regions. Q928* is nonsense, not an indel. Therefore, BP3 is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines for BP4, synonymous or non-coding variants with no splice impact support benign. Q928* is a nonsense variant. Therefore, BP4 is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP5 applies when a variant is found in a case with an alternative molecular cause. No alternate cause is documented. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 applies when a variant is reported as benign by a reputable source without available evidence. Q928* is not so reported. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines for BP7, synonymous or non-coding conserved sites with low conservation support benign. Q928* is not synonymous. Therefore, BP7 is not applied.