The PIK3CA c.2782C>T (p.Gln928Ter; p.Q928*) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is within the Brain Malformations VCEP PM2_Supporting threshold of at most 1 occurrence in population data and below the BS1 (>0.0185%) and BA1 (>0.0926%) thresholds.2 The variant lies within the PIK3CA kinase domain approved for PM1_Supporting by the Brain Malformations VCEP (amino acids 797-1068), supporting location in a critical functional region.3 SpliceAI predicts no significant splice impact for this variant with a maximum delta score of 0.10, although PP3 and BP4 are not applicable to this nonsense variant under the Brain Malformations VCEP specifications.4
Final classification
VUS
PM1PM2
PIK3CA
c.2782C>T
p.Gln928Ter
This variant
The PIK3CA c.2782C>T (p.Gln928Ter; p.Q928*) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.
Generic ACMG/AMP final classification combination rules were used as fallback because the retrieved Brain Malformations Specification final-classification framework was present but not complete for direct application.
Classification rationale
PM1PM2
VUS
PIK3CA c.2782C>T
PM1 + PM2
→
VUS
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_006218.4 · variants mapped to exon structure
PIK3CA
NM_006218.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 10 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
PM1
Supporting
review
Pathogenic
This variant truncates PIK3CA at p.(Gln928Ter), which lies within the PIK3CA kinase domain approved by the Brain Malformations VCEP for PM1_Supporting (amino acids 797-1068). This location is within a critical functional domain, so PM1 is met at supporting strength.
The Brain Malformations VCEP allows PM1 at supporting strength for variants in approved functional domains.Table 4 lists a PIK3CA kinase domain spanning amino acids 797-1068.The variant protein consequence is p.(Gln928Ter)/p.(Q928*).
PM2
Supporting
review
Pathogenic
This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed allele count is 0, which is within the Brain Malformations VCEP PM2_Supporting threshold of at most 1 occurrence in population data. PM2 is met at supporting strength.
PM2_Supporting applies when the variant is absent or rare in controls, with one person maximum.Absent from gnomAD v2.1.Absent from gnomAD v4.1.
Assessed · not applied
· 5 not met · 5 not assessed
Pathogenic
PS1
This nonsense variant results in p.(Gln928Ter), but no previously established pathogenic variant with the same amino acid change was identified.
PS2
No case-specific parental testing or multi-tissue allele fraction data were identified.
PS4
This variant is absent from gnomAD and therefore satisfies the population prerequisite for PS4 consideration, but no phenotype-based case evidence was identified to contribute PS4 points.
PS3
No well-established functional studies supporting a damaging effect for this specific variant were identified.
Benign
BS2
This variant is absent from gnomAD v2.1 and gnomAD v4.1, so it does not meet the VCEP BS2 threshold of at least 3 homozygotes in population data.
BP5
No evidence was identified showing that this variant was observed in an individual with an alternate molecular basis for disease in a different gene.
BP2
No evidence was identified showing that this variant was observed in cis or trans with a known pathogenic variant in PIK3CA.
BS3
No well-established functional studies showing no damaging effect for this specific variant were identified.
BA1
This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed allele frequency is 0, which is below the Brain Malformations VCEP BA1 threshold of greater than 0.0926%.
BS1
This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed allele frequency is 0, which is below the Brain Malformations VCEP BS1 threshold of greater than 0.0185%.
N/A · 16
BS4 · PP4 · PP3 · PVS1 · PP5 · BP7 · BP4 · BP3 · BP1 · PP2 · PP1 · PM5 · PM4 · PM3 · BP6 · PM6
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10).
Functional
Unknown Oncogenic Effect
OncoKB oncogenicity for this specific variant: Unknown Oncogenic Effect (variant has not been individually curated).
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links