About PIK3CA
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PIK3CA c.335T>C, p.(Ile112Thr)
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: 1
Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and gnomAD v4.1, with 0 observed individuals across both datasets, which satisfies the Brain Malformations VCEP PM2 threshold of absent or rare in controls with no more than 1 person observed.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
Brain Malformations Specification Tavtigian point framework v1.1.0 point-based framework: PM2 supporting (+1) = 1 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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
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.
Context only
ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded
No standalone functional evidence summary is recorded in evidence_summary.functional.
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 lies 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 · 5 not met · 8 not assessed · 14 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.335T>C (p.Ile112Thr, p.I112T) variant has not been reported in ClinVar.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting PM2_Supporting under the Brain Malformations VCEP rule for variants observed in no more than 1 person.
The p.Ile112Thr change affects residue 112, which is outside the PIK3CA Table 4 approved kinase-domain intervals of amino acids 322-483 and 797-1068, so PM1 is not met.
Computational data show no predicted splice impact by SpliceAI (max delta score 0.00), with REVEL 0.39 and BayesDel 0.238394, but under this VCEP PP3 is not applicable and BP4 is restricted to synonymous, intronic, or UTR variants.
No criteria match.
Met · 1
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1, with 0 observed individuals across both datasets, which satisfies the Brain Malformations VCEP PM2 threshold of absent or rare in controls with no more than 1 person observed. Details ▾Hide ▴
Rule
PM2_Supporting may be awarded when the variant is absent or rare in controls with at most one observed person.
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: absent
- PM2 threshold: <=1 observed person
Sources
Not met · 5 · evaluated, threshold not reached
PS4 This variant meets PM2_Supporting because it is absent from gnomAD, but no affected-case phenotype point data were identified to reach the VCEP PS4 thresholds of at least 0.5 points for supporting evidence. Details ▾Hide ▴
Rule
PS4 requires PM2 first and at least 0.5 phenotype points for PS4_Supporting under the Brain Malformations VCEP point system.
Evidence considered
- PM2 prerequisite satisfied by absence from gnomAD v2.1 and v4.1
- ClinVar: no entry identified for this variant
- Literature screen: no PMIDs identified
Still missing
- No published affected cases with phenotype point assignments were identified.
- No case-enrichment or exact variant recurrence evidence was identified that could be translated into Table 2A and Table 2B points.
Sources
PM1 The p.Ile112Thr change affects residue 112, which is outside the PIK3CA Table 4 approved kinase-domain intervals of amino acids 322-483 and 797-1068, so PM1 is not met. Available hotspot evidence was marked uncertain and does not establish a validated hotspot at codon 112. Details ▾Hide ▴
Rule
PM1_Supporting may be awarded for variants in approved Table 4 critical domains.
Evidence considered
- Protein consequence: p.Ile112Thr
- PIK3CA Table 4 approved domains: aa 322-483 and aa 797-1068
- Cancer Hotspots assessment: uncertain for residue I112
Still missing
- No verified residue-level evidence was identified showing codon 112 is an established hotspot or critical benign-variant-depleted region.
Sources
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its observed allele frequency is 0%, which is below the VCEP BA1 threshold of greater than 0.0926%. Details ▾Hide ▴
Rule
BA1 requires allele frequency >0.0926% under this VCEP.
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: absent
- BA1 threshold: >0.0926%
Sources
BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its observed allele frequency is 0%, which is below the VCEP BS1 threshold of greater than 0.0185%. Details ▾Hide ▴
Rule
BS1 requires allele frequency >0.0185% under this VCEP.
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: absent
- BS1 threshold: >0.0185%
Sources
BS2 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so there are 0 observed homozygotes, which is below the VCEP BS2 threshold of at least 3 homozygotes or at least 3 well-phenotyped unaffected heterozygous family members. Details ▾Hide ▴
Rule
Award BS2 if >=3 homozygotes are present in population data or >=3 well-phenotyped unaffected heterozygous family members are identified.
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: absent
- BS2 threshold: >=3 homozygotes or >=3 unaffected heterozygous family members
Still missing
- No well-phenotyped unaffected family data were identified.
Sources
Not assessed · 8 · no assessment recorded
PS1 No previously established pathogenic variant producing the same amino acid change was identified in the available sources, so PS1 could not be assessed. Details ▾Hide ▴
Rule
PS1 requires the same amino acid change as a previously established pathogenic variant.
Evidence considered
- ClinVar: no entry identified for NM_006218.4:c.335T>C
Still missing
- Direct same-amino-acid comparator evidence was not identified.
- Additional exact-codon literature or database review would be needed to confirm whether a pathogenic alternate nucleotide change to p.Ile112Thr has been reported.
Sources
PS2 No confirmed de novo result, parental testing, or tissue mosaicism data were identified for this variant, so PS2 could not be assessed. Details ▾Hide ▴
Rule
PS2_Strong requires both confirmed parental absence and tissue-distribution evidence; PS2_Moderate requires one of those elements under the VCEP rule.
Evidence considered
- Brain Malformations VCEP PS2 requires parental and/or tissue mosaic evidence
- ClinVar: no entry identified for this variant
Still missing
- No report was identified showing absence from both parents with confirmed maternity and paternity.
- No report was identified showing a higher allele fraction in affected tissue than in another tissue.
Sources
PS3 No validated functional study was identified showing an abnormal effect of p.Ile112Thr in an assay meeting the Brain Malformations VCEP PS3 requirements, so PS3 could not be assessed. Details ▾Hide ▴
Rule
PS3 requires well-established functional studies showing a damaging effect and meeting the VCEP quality specifications.
Evidence considered
- Literature screen: no PMIDs identified
- OncoKB lookup did not yield usable variant-specific functional evidence
Still missing
- No exact-variant functional assay result was identified.
- No assay details were identified that could be evaluated against the VCEP PS3 quality requirements.
Sources
PM5 No validated same-residue pathogenic comparator variant was identified for codon 112, so PM5 could not be assessed from the available evidence. Details ▾Hide ▴
Rule
PM5 requires a different pathogenic missense change at the same amino acid residue.
Evidence considered
- PM5 framework mode: classic same-residue missense
- PM5 candidate summary: 0 same-residue candidates identified
Still missing
- No expert-panel or other established pathogenic missense comparator at the same residue was identified.
- The available PM5 candidate artifact did not provide a usable same-residue comparator review for this missense change.
Sources
cspec ↗pm5_candidates
PP2 PP2 may be applicable for PIK3CA missense variants when the missense constraint z-score is greater than 3.09, but the required gene-level constraint value was not identified in the available evidence, so PP2 could not be assessed. Details ▾Hide ▴
Rule
PP2_Supporting may be awarded for PIK3CA if the missense constraint z-score is >3.09.
Evidence considered
- Brain Malformations VCEP PP2 rule: award if missense constraint z-score >3.09
Still missing
- The PIK3CA missense constraint z-score was not provided in the available materials.
Sources
BS3 No validated functional study was identified showing normal or non-damaging function for p.Ile112Thr, so BS3 could not be assessed. Details ▾Hide ▴
Rule
BS3 requires well-established functional studies showing no damaging effect.
Evidence considered
- Literature screen: no PMIDs identified
- OncoKB lookup did not yield usable variant-specific functional evidence
Still missing
- No exact-variant benign functional assay result was identified.
Sources
BP2 No phase data were identified showing this variant in cis or trans with a known pathogenic PIK3CA variant, so BP2 could not be assessed. Details ▾Hide ▴
Rule
BP2 may be used when the variant is observed in cis or trans with a known pathogenic variant in the same gene.
Evidence considered
- Brain Malformations VCEP BP2 retained
- ClinVar: no entry identified for this variant
Still missing
- No case-level phasing information was identified.
Sources
BP5 No evidence was identified showing an alternate molecular explanation for the reported phenotype in a person carrying this variant, so BP5 could not be assessed. Details ▾Hide ▴
Rule
BP5 may be used when an alternate molecular basis for disease is established.
Evidence considered
- Brain Malformations VCEP BP5 retained
- ClinVar: no entry identified for this variant
Still missing
- No case-level genotype-phenotype reports with an alternate established diagnosis were identified.
Sources
Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable under the Brain Malformations VCEP framework for PIK3CA because the disease mechanism is gain of function, and this variant is also a missense change rather than a canonical null variant. Details ▾Hide ▴
Rule
PVS1 is not applicable for this VCEP.
Evidence considered
- Brain Malformations VCEP: PVS1 marked not applicable for PIK3CA
- Generic PVS1 scaffold: variant is not a nonsense
- frameshift
- or canonical +/-1
- 2 splice variant
- Protein consequence: p.Ile112Thr missense
Sources
PM3 N/APM3 is not applicable under the Brain Malformations VCEP framework for this gene-disease context. Details ▾Hide ▴
Rule
PM3 is not applicable for this VCEP.
Evidence considered
- Brain Malformations VCEP: PM3 marked not applicable
Sources
PM4 N/APM4 is not applicable under the Brain Malformations VCEP framework for this gene-disease context. Details ▾Hide ▴
Rule
PM4 is not applicable for this VCEP.
Evidence considered
- Brain Malformations VCEP: PM4 marked not applicable
Sources
PM6 N/APM6 is not applicable under the Brain Malformations VCEP framework for this gene-disease context. Details ▾Hide ▴
Rule
PM6 is not applicable for this VCEP.
Evidence considered
- Brain Malformations VCEP: PM6 marked not applicable
Sources
PP1 N/APP1 is not applicable under the Brain Malformations VCEP framework for this gene-disease context. Details ▾Hide ▴
Rule
PP1 is not applicable for this VCEP.
Evidence considered
- Brain Malformations VCEP: PP1 marked not applicable
Sources
PP3 N/APP3 is not applicable under the Brain Malformations VCEP framework for this gene-disease context. Available computational results include SpliceAI max delta score 0.00, REVEL 0.39, and BayesDel 0.238394, but these do not create a PP3 call when the VCEP has marked PP3 not applicable. Details ▾Hide ▴
Rule
PP3 is not applicable for this VCEP.
Evidence considered
- Brain Malformations VCEP: PP3 marked not applicable
- SpliceAI max delta score: 0.00
- REVEL: 0.39
- BayesDel: 0.238394
Sources
PP4 N/APP4 is not applicable under the Brain Malformations VCEP framework for this gene-disease context. Details ▾Hide ▴
Rule
PP4 is not applicable for this VCEP.
Evidence considered
- Brain Malformations VCEP: PP4 marked not applicable
Sources
PP5 N/APP5 is not applicable under the Brain Malformations VCEP framework for this gene-disease context. Details ▾Hide ▴
Rule
PP5 is not applicable for this VCEP.
Evidence considered
- Brain Malformations VCEP: PP5 marked not applicable
Sources
BS4 N/ABS4 is not applicable under the Brain Malformations VCEP framework for this gene-disease context. Details ▾Hide ▴
Rule
BS4 is not applicable for this VCEP.
Evidence considered
- Brain Malformations VCEP: BS4 marked not applicable
Sources
BP1 N/ABP1 is not applicable under the Brain Malformations VCEP framework for PIK3CA. Details ▾Hide ▴
Rule
BP1 is not applicable for this VCEP.
Evidence considered
- Brain Malformations VCEP: BP1 marked not applicable
Sources
BP3 N/ABP3 is not applicable under the Brain Malformations VCEP framework for this gene-disease context. Details ▾Hide ▴
Rule
BP3 is not applicable for this VCEP.
Evidence considered
- Brain Malformations VCEP: BP3 marked not applicable
Sources
BP4 N/ABP4 is not applicable because this is a missense variant, whereas the VCEP restricts BP4 to synonymous, non-canonical intronic, or UTR variants assessed for lack of splice impact. SpliceAI predicts no splice effect with a max delta score of 0.00, but that does not create a BP4 call for this missense change. Details ▾Hide ▴
Rule
BP4 applies only to synonymous, intronic non-canonical splice, and UTR variants when two of three splice tools predict no effect.
Evidence considered
- Protein consequence: p.Ile112Thr missense
- SpliceAI max delta score: 0.00
- Brain Malformations VCEP BP4 applicability restriction
Sources
BP6 N/ABP6 is not applicable under the Brain Malformations VCEP framework for this gene-disease context. Details ▾Hide ▴
Rule
BP6 is not applicable for this VCEP.
Evidence considered
- Brain Malformations VCEP: BP6 marked not applicable
Sources
BP7 N/ABP7 is not applicable because this is a missense variant, whereas the VCEP limits BP7 to synonymous, non-canonical intronic, or UTR variants. Details ▾Hide ▴
Rule
BP7 applies to synonymous, intronic non-canonical splice, and UTR variants with low conservation under this VCEP.
Evidence considered
- Protein consequence: p.Ile112Thr missense
- SpliceAI max delta score: 0.00
Sources
Identifiers
- Gene
- PIK3CA
- Transcript
- NM_006218.4
- Coding (HGVS c.)
- NM_006218.4:c.335T>C
- Protein (HGVS p.)
- NP_006209.2:p.(Ile112Thr)
- GRCh38
- chr3:179199160 T>C
- GRCh37
- chr3:178916948 T>C
Gene diagram
Every interpreted variant in PIK3CA, mapped onto the exon structure of NM_006218.4. Select a row to find it on the plot.
PIK3CANM_006218.4
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
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 N/APP3 is not applicable under the Brain Malformations VCEP framework for this gene-disease context. Available computational results include SpliceAI max delta score 0.00, REVEL 0.39, and BayesDel 0.238394, but these do not create a PP3 call when the VCEP has marked PP3 not applicable. Details ▾Hide ▴
Rule
PP3 is not applicable for this VCEP.
Evidence considered
- Brain Malformations VCEP: PP3 marked not applicable
- SpliceAI max delta score: 0.00
- REVEL: 0.39
- BayesDel: 0.238394
Sources
BP4 N/ABP4 is not applicable because this is a missense variant, whereas the VCEP restricts BP4 to synonymous, non-canonical intronic, or UTR variants assessed for lack of splice impact. SpliceAI predicts no splice effect with a max delta score of 0.00, but that does not create a BP4 call for this missense change. Details ▾Hide ▴
Rule
BP4 applies only to synonymous, intronic non-canonical splice, and UTR variants when two of three splice tools predict no effect.
Evidence considered
- Protein consequence: p.Ile112Thr missense
- SpliceAI max delta score: 0.00
- Brain Malformations VCEP BP4 applicability restriction
Sources
BP7 N/ABP7 is not applicable because this is a missense variant, whereas the VCEP limits BP7 to synonymous, non-canonical intronic, or UTR variants. Details ▾Hide ▴
Rule
BP7 applies to synonymous, intronic non-canonical splice, and UTR variants with low conservation under this VCEP.
Evidence considered
- Protein consequence: p.Ile112Thr missense
- SpliceAI max delta score: 0.00
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.39. BayesDel score = 0.238394.
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
Captured gnomAD v4.1 source record
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 ↗
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/?term=NM_006218.4%3Ac.335T%3EC
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-178916948-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-179199160-T-C?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006218.4%3Ac.335T…
- OncoKB ↗www.oncokb.org/gene/PIK3CA/I112T
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PIK3CA+c.335T%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
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.39. BayesDel score = 0.238394.
Somatic
This variant lies in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant lies in a statistically significant hotspot.