About PIK3CA
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PIK3CA c.2040T>C, p.(Val680=)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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.
01The reasoning
How it was classified
The recorded framework is ClinGen PIK3CA VCEP v1.1.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 0
Benign evidence criteria: 1
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 1
BP6Supporting
BP6 · supporting
Expert panel ClinGen Brain Malformations Variant Curation Expert Panel classified as Likely benign.
Recorded classification: Uncertain significance
Brain Malformations Specification Tavtigian point framework v1.1.0 point-based framework: no point-contributing criteria = 0 points, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
40 / 1,612,688 alleles
gnomAD v4.1: 40 / 1,612,688 alleles. Recorded AF 2.48033e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 8.0351e-06; MAF= 0.00080%, 2/248908 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.77001e-05; MAF= 0.00177%, 2/112994 alleles, homozygotes = 0); grpmax FAF= 2.94e-06.
No listed criterion applied
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
No listed criterion applied
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Functional evidence
Statement recorded
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen PIK3CA VCEP v1.1.0, with the data and sources behind each one.
28 criteria with recorded statuses: 1 met · 7 not met · 7 not assessed · 13 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The PIK3CA c.2040T>C (p.Val680=) variant has been reported in ClinVar and is classified as likely benign by the ClinGen Brain Malformations Variant Curation Expert Panel.
This variant is present in gnomAD at 0.00080% in v2.1 (2/248908 alleles) and 0.00248% in v4.1 (40/1612688 alleles), which is below the VCEP BS1 threshold of 0.0185% and BA1 threshold of 0.0926% but exceeds the VCEP PM2 one-person maximum.
SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01, although additional VCEP-specified splicing predictors and a conservation score were not identified for BP4 and BP7 assessment.
No criteria match.
Met · 1
Not met · 7 · evaluated, threshold not reached
PS1 This is a synonymous variant, p.(Val680=), and no evidence was identified that it results in the same established pathogenic amino acid change as a previously classified pathogenic variant. Details ▾Hide ▴
PS4 The VCEP requires PM2 before PS4 can be used. This variant exceeds the VCEP PM2 one-person maximum because it is present in gnomAD v2.1 at 2/248908 alleles and in gnomAD v4.1 at 40/1612688 alleles, and no point-based affected-case evidence was identified for this exact variant. Details ▾Hide ▴
Rule
VCEP PS4 requires PM2 and phenotype-point thresholds
Evidence considered
- VCEP PS4 requires PM2 first.
- gnomAD v2.1: 2/248908 alleles.
- gnomAD v4.1: 40/1612688 alleles.
Still missing
- No exact affected-case point tally under the VCEP PS4 table was identified.
Sources
PM1 The VCEP allows PM1_Supporting for PIK3CA variants in approved Table 4 domains at amino acids 322-483 or 797-1068. This synonymous variant affects codon 680, which is outside those approved domains. Details ▾Hide ▴
Rule
VCEP PM1_Supporting domain rule for PIK3CA
Evidence considered
- Protein consequence is p.(Val680=).
- PIK3CA Table 4 approved domains are amino acids 322-483 and 797-1068.
Sources
PM2 The VCEP applies PM2 only at Supporting strength and limits it to a maximum of one person in controls. This variant is present in gnomAD v2.1 at 2/248908 alleles and in gnomAD v4.1 at 40/1612688 alleles, so PM2 is not met. Details ▾Hide ▴
Rule
VCEP PM2_Supporting one-person maximum
Evidence considered
- VCEP PM2 uses a one-person maximum.
- gnomAD v2.1 total AF 8.0351e-06.
- gnomAD v4.1 total AF 2.48033e-05.
Sources
BA1 The VCEP BA1 threshold is >0.0926%. This variant is present in gnomAD v4.1 at 0.00248% and in gnomAD v2.1 at 0.00080%, both well below the BA1 threshold. Details ▾Hide ▴
Rule
VCEP BA1 population threshold
Evidence considered
- BA1 threshold >0.0926%.
- gnomAD v4.1 AF 0.00248%.
- gnomAD v2.1 AF 0.00080%.
Sources
BS1 The VCEP BS1 threshold is >0.0185%. This variant is present in gnomAD v4.1 at 0.00248% and in gnomAD v2.1 at 0.00080%, both below the BS1 threshold. Details ▾Hide ▴
Rule
VCEP BS1 population threshold
Evidence considered
- BS1 threshold >0.0185%.
- gnomAD v4.1 AF 0.00248%.
- gnomAD v2.1 AF 0.00080%.
Sources
BS2 The VCEP applies BS2 when there are at least 3 homozygotes in population data or at least 3 well-phenotyped unaffected heterozygous family members. This variant has 0 homozygotes in gnomAD v2.1 and 0 homozygotes in gnomAD v4.1, and no qualifying family data were identified. Details ▾Hide ▴
Rule
VCEP BS2 population/family rule
Evidence considered
- BS2 requires at least 3 homozygotes or 3 unaffected heterozygous family members.
- gnomAD v2.1 homozygotes: 0.
- gnomAD v4.1 homozygotes: 0.
Still missing
- No well-phenotyped unaffected family-member data were identified.
Sources
Not assessed · 7 · no assessment recorded
PS2 No confirmed de novo evidence was identified for this variant, and no tissue-distribution data were identified showing a higher allele fraction in affected tissue than in another tissue as required by the VCEP framework. Details ▾Hide ▴
Rule
VCEP PS2 mosaic/de novo criteria
Evidence considered
- VCEP PS2 requires confirmed parental absence and/or tissue distribution evidence for mosaicism.
Still missing
- Confirmed maternity and paternity with absent parental testing were not identified.
- Variant allele fraction data across affected and unaffected tissues were not identified.
Sources
PS3 No published functional or RNA study was identified showing a damaging effect of this exact synonymous variant under the VCEP/SVI assay standards. Details ▾Hide ▴
Rule
VCEP/SVI functional evidence requirements for PS3
Evidence considered
- No exact-variant functional evidence was identified in the reviewed sources.
Still missing
- No exact-variant RNA assay was identified.
- No exact-variant functional assay was identified.
Sources
BS3 No published functional or RNA study was identified showing that this exact variant has no damaging effect under the VCEP/SVI assay standards. Details ▾Hide ▴
Rule
VCEP/SVI functional evidence requirements for BS3
Evidence considered
- No exact-variant benign functional evidence was identified in the reviewed sources.
Still missing
- No exact-variant benign functional assay was identified.
- No exact-variant benign RNA assay was identified.
Sources
BP2 No observation was identified showing this variant in cis or in trans with a known pathogenic PIK3CA variant. Details ▾Hide ▴
Rule
VCEP BP2 cis/trans rule
Evidence considered
- VCEP BP2 requires a cis or trans observation with a known pathogenic variant.
Still missing
- No phase data with a known pathogenic PIK3CA variant were identified.
Sources
BP4 This synonymous non-canonical variant has a low SpliceAI score, with a maximum delta score of 0.01, which is consistent with no significant splice effect. However, the VCEP requires no-impact predictions from 2 of 3 specified splicing tools, and only SpliceAI evidence was identified. Details ▾Hide ▴
Rule
VCEP BP4 splicing-predictor rule for synonymous variants
Evidence considered
- SpliceAI max delta score 0.01.
- VCEP BP4 requires 2 of 3 splicing tools showing no impact.
Still missing
- No varSEAK result was identified.
- No MaxEntScan result was identified.
Sources
BP5 No evidence was identified that this variant was found in an individual with an alternate molecular explanation for the phenotype. Details ▾Hide ▴
Rule
VCEP BP5 alternate molecular basis rule
Evidence considered
- BP5 requires an alternate molecular basis for disease.
Still missing
- No alternate molecular diagnosis data were identified.
Sources
BP7 This is a synonymous variant outside the canonical splice consensus, but BP7 requires a non-conserved nucleotide with PhyloP <0.1. No conservation score was identified to confirm that requirement. Details ▾Hide ▴
Rule
VCEP BP7 conservation rule for synonymous variants
Evidence considered
- Variant is synonymous and not at a canonical splice site.
- VCEP BP7 requires PhyloP <0.1.
Still missing
- No PhyloP conservation score was identified.
Sources
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThe Brain Malformations VCEP specifies that PVS1 is not applicable for PIK3CA because the relevant disease mechanism is gain of function rather than loss of function. Details ▾Hide ▴
Rule
VCEP PVS1 not applicable for PIK3CA gain-of-function disease mechanism
Evidence considered
- Brain Malformations VCEP guidance lists PVS1 as not applicable for PIK3CA.
Sources
PM3 N/AThe Brain Malformations VCEP does not apply PM3 in this framework. Details ▾Hide ▴
PM4 N/AThe Brain Malformations VCEP does not apply PM4 in this framework. Details ▾Hide ▴
PM5 N/AThe governing PM5 framework for this gene uses classic same-residue missense logic, and this variant is synonymous rather than missense. Details ▾Hide ▴
Rule
Classic same-residue missense PM5
Evidence considered
- PM5 candidate review marked the variant as not eligible for classic same-residue missense PM5.
Sources
pm5_candidatescspec ↗
PM6 N/AThe Brain Malformations VCEP does not apply PM6 in this framework. Details ▾Hide ▴
PP1 N/AThe Brain Malformations VCEP does not apply PP1 for this framework. Details ▾Hide ▴
PP2 N/AThe VCEP PP2 rule is intended for missense variants using missense constraint, and this variant is synonymous. Details ▾Hide ▴
Rule
VCEP PP2 missense-constraint rule
Evidence considered
- Protein consequence is p.(Val680=).
- VCEP PP2 applies to missense variants.
Sources
PP3 N/AThe Brain Malformations VCEP specifies that PP3 is not applicable for these gain-of-function disorders because traditional pathogenicity predictors are not validated for this mechanism. Details ▾Hide ▴
Rule
VCEP PP3 not applicable for gain-of-function context
Evidence considered
- VCEP lists PP3 as not applicable for this framework.
Sources
PP4 N/AThe Brain Malformations VCEP specifies that PP4 is not applicable because phenotype specificity is incorporated into PS4. Details ▾Hide ▴
PP5 N/APP5 is not used in this framework. Details ▾Hide ▴
BS4 N/AThe Brain Malformations VCEP does not apply BS4 in this framework. Details ▾Hide ▴
BP1 N/AThe Brain Malformations VCEP does not apply BP1 for PIK3CA because the disease mechanism is gain of function rather than a gene in which truncating variants are typically pathogenic. Details ▾Hide ▴
Rule
VCEP BP1 not applicable
Evidence considered
- VCEP guidance states BP1 is not applicable in this framework.
Sources
BP3 N/AThe Brain Malformations VCEP does not apply BP3 in this framework. Details ▾Hide ▴
Identifiers
- Gene
- PIK3CA
- Transcript
- NM_006218.2
- Coding (HGVS c.)
- NM_006218.2:c.2040T>C
- Protein (HGVS p.)
- NP_006209.2:p.(Val680=)
- GRCh38
- chr3:179221010 T>C
- GRCh37
- chr3:178938798 T>C
Gene diagram
Every interpreted variant in PIK3CA, mapped onto the exon structure of NM_006218.2. Select a row to find it on the plot.
PIK3CANM_006218.2
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in PIK3CA
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
40 / 1,612,688 alleles
AF 2.48e-05 · 0 homozygotes · FAF 2.39e-05
gnomAD v2.1
2 / 248,908 alleles
AF 8.04e-06 · 0 homozygotes · FAF 2.94e-06
By genetic ancestry
gnomAD v4.1
AF 2.5e-05 · 40 / 1,612,688 alleles · 0 hom · FAF 2.4e-05
| European (non-Finnish)38 / 1,179,176 | 3.2e-05 |
| Remaining individuals1 / 62,406 | 1.6e-05 |
| African/African American1 / 74,878 | 1.3e-05 |
0 alternate alleles recorded in 7 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 8e-06 · 2 / 248,908 alleles · 0 hom · FAF 2.9e-06
| European (non-Finnish)2 / 112,994 | 1.8e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 2.48033e-05; MAF= 0.00248%, 40/1612688 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.22259e-05; MAF= 0.00322%, 38/1179176 alleles, homozygotes = 0); grpmax FAF= 2.395e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 8.0351e-06; MAF= 0.00080%, 2/248908 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.77001e-05; MAF= 0.00177%, 2/112994 alleles, homozygotes = 0); grpmax FAF= 2.94e-06.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 This synonymous non-canonical variant has a low SpliceAI score, with a maximum delta score of 0.01, which is consistent with no significant splice effect. However, the VCEP requires no-impact predictions from 2 of 3 specified splicing tools, and only SpliceAI evidence was identified. Details ▾Hide ▴
Rule
VCEP BP4 splicing-predictor rule for synonymous variants
Evidence considered
- SpliceAI max delta score 0.01.
- VCEP BP4 requires 2 of 3 splicing tools showing no impact.
Still missing
- No varSEAK result was identified.
- No MaxEntScan result was identified.
Sources
BP7 This is a synonymous variant outside the canonical splice consensus, but BP7 requires a non-conserved nucleotide with PhyloP <0.1. No conservation score was identified to confirm that requirement. Details ▾Hide ▴
Rule
VCEP BP7 conservation rule for synonymous variants
Evidence considered
- Variant is synonymous and not at a canonical splice site.
- VCEP BP7 requires PhyloP <0.1.
Still missing
- No PhyloP conservation score was identified.
Sources
PP3 N/AThe Brain Malformations VCEP specifies that PP3 is not applicable for these gain-of-function disorders because traditional pathogenicity predictors are not validated for this mechanism. Details ▾Hide ▴
Rule
VCEP PP3 not applicable for gain-of-function context
Evidence considered
- VCEP lists PP3 as not applicable for this framework.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
40 / 1,612,688 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/467907148
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/456534/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-178938798-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-179221010-T-C?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006218.2%3Ac.2040…
- OncoKB ↗www.oncokb.org/gene/PIK3CA/V680=
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PIK3CA+c.2040T%3EC
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 2.48033e-05; MAF= 0.00248%, 40/1612688 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.22259e-05; MAF= 0.00322%, 38/1179176 alleles, homozygotes = 0); grpmax FAF= 2.395e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 8.0351e-06; MAF= 0.00080%, 2/248908 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.77001e-05; MAF= 0.00177%, 2/112994 alleles, homozygotes = 0); grpmax FAF= 2.94e-06.
ClinVar
This variant has been reported in ClinVar as Likely benign (2 clinical laboratories) and as Likely benign by ClinGen Brain Malformations Variant Curation Expert Panel (expert panel). (ClinVarID = 456534)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
Functional
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.