About PIK3CA
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PIK3CA c.1265del, p.(Leu422TrpfsTer6)
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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM1Supporting
PM1 · supporting
The altered residue Leu422 lies within the approved PIK3CA kinase-domain interval spanning amino acids 322-483 in the Brain Malformations VCEP specification. This location is a listed critical functional domain, which supports PM1 at Supporting strength.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, which is below the Brain Malformations VCEP PM2 threshold requiring absence or rarity in controls with no more than one person observed. These data support PM2 at Supporting strength.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
Brain Malformations Specification Tavtigian point framework from the CSPEC/VCEP final-classification framework: PM1_Supporting (+1) and PM2_Supporting (+1) for a total of 2 points.
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 ↗
Functional evidence
Statement recorded
OncoKB oncogenicity for this specific variant: Unknown Oncogenic Effect (variant has not been individually curated).
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: 2 met · 4 not met · 5 not assessed · 17 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.1265del (p.(Leu422TrpfsTer6)) variant has not been reported in ClinVar.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting PM2 at Supporting strength, and its observed population frequency of 0% is below the VCEP BS1 threshold of >0.0185% and BA1 threshold of >0.0926%.
The altered residue lies within the approved PIK3CA kinase-domain interval spanning amino acids 322-483, which is a Brain Malformations VCEP critical functional domain and supports PM1_Supporting.
SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.07, although computational pathogenicity criteria are not applied for PIK3CA gain-of-function interpretation in this VCEP framework.
No criteria match.
Met · 2
PM1 SupportingThe altered residue Leu422 lies within the approved PIK3CA kinase-domain interval spanning amino acids 322-483 in the Brain Malformations VCEP specification. This location is a listed critical functional domain, which supports PM1 at Supporting strength. Details ▾Hide ▴
Rule
PM1_Supporting
Evidence considered
- Protein consequence is p.(Leu422TrpfsTer6).
- Leu422 falls within the VCEP-approved kinase domain AA 322-483.
Sources
cspec ↗vcep_c_l_i_n_g_e_n___b_r_a_i_n_m_a_l_f_o_r_m___a_c_m_g___s_p_e_c_i_f_i_c_a_t_i_o_n_s___v_1___1
PM2 SupportingThis variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, which is below the Brain Malformations VCEP PM2 threshold requiring absence or rarity in controls with no more than one person observed. These data support PM2 at Supporting strength. Details ▾Hide ▴
Rule
PM2_Supporting
Evidence considered
- gnomAD v2.1: absent.
- gnomAD v4.1: absent.
- VCEP PM2 is Supporting for absent/rare control data.
Sources
Not met · 4 · evaluated, threshold not reached
PS4 This variant meets the PM2 population prerequisite because it is absent from gnomAD v2.1 and v4.1, but the available case-level observation data do not reach the VCEP PS4 threshold. Only a single somatic cancer observation was identified and no phenotype-pointed germline case series were identified, so the evidence does not reach the minimum PS4_Supporting threshold of 0.5 points. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
- VCEP PS4 requires PM2 first and uses phenotype-point thresholds.
Still missing
- Reported affected individuals with VCEP-qualifying phenotypes
- Phenotype point assignments under VCEP Table 2A
Sources
BA1 This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, so the observed population frequency is 0%, which is below the Brain Malformations VCEP BA1 threshold of greater than 0.0926%. BA1 is not met. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent.
- gnomAD v4.1: absent.
- BA1 threshold >0.0926% in the VCEP specification.
Sources
BS1 This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, so the observed population frequency is 0%, which is below the Brain Malformations VCEP BS1 threshold of greater than 0.0185%. BS1 is not met. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent.
- gnomAD v4.1: absent.
- BS1 threshold >0.0185% in the VCEP specification.
Sources
BS2 BS2 requires at least 3 homozygotes in gnomAD or at least 3 heterozygous occurrences in well-phenotyped family members. This variant is absent from gnomAD and no such family observations were identified, so BS2 is not met. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent.
- gnomAD v4.1: absent.
- VCEP BS2 threshold is ≥3 qualifying observations.
Still missing
- Well-phenotyped family data
Sources
Not assessed · 5 · no assessment recorded
PS2 No confirmed de novo or tissue-mosaic data were identified. Available evidence does not show absence from both parents with confirmed maternity and paternity, or a higher allele fraction in affected tissue than in another tissue, so PS2 cannot be assessed from the current evidence. Details ▾Hide ▴
Evidence considered
- VCEP requires confirmed parental absence and/or tissue-specific mosaic evidence for PS2.
Still missing
- Parental testing results
- Multi-tissue allele fraction data
Sources
PS3 No validated functional studies demonstrating an abnormal effect of this specific variant were identified, so PS3 is not assessed. Details ▾Hide ▴
Evidence considered
- No functional publications were identified for this variant.
Still missing
- Well-validated variant-specific functional assay data
Sources
BS3 No well-validated functional studies demonstrating a normal effect for this specific variant were identified, so BS3 is not assessed. Details ▾Hide ▴
Evidence considered
- No functional publications were identified for this variant.
Still missing
- Well-validated variant-specific benign functional assay data
Sources
BP2 No evidence was identified showing this variant in cis or trans with a known pathogenic variant in PIK3CA, so BP2 is not assessed. Details ▾Hide ▴
Evidence considered
- VCEP allows BP2 for cis or trans observations with a known pathogenic variant.
Still missing
- Phase data with a known pathogenic PIK3CA variant
Sources
BP5 No evidence was identified showing an alternate molecular explanation that would account for the phenotype independently of this variant, so BP5 is not assessed. Details ▾Hide ▴
Evidence considered
- No alternate molecular explanation was identified in the available evidence.
Still missing
- Documented alternate molecular diagnosis or explanatory variant
Sources
Not applicable · 17· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis frameshift variant would ordinarily trigger generic loss-of-function review, but the Brain Malformations VCEP specifies that PVS1 is not applicable for PIK3CA because the relevant disease mechanism is gain of function. Details ▾Hide ▴
Evidence considered
- PIK3CA Brain Malformations VCEP marks PVS1 as not applicable.
- Generic PVS1 scaffold is superseded by the gene-specific VCEP rule for this gene-disease context.
Sources
PS1 N/APS1 is defined for a variant that creates the same amino acid substitution as a previously established pathogenic variant. This variant is a frameshift, not an amino acid substitution, so PS1 is not applicable. Details ▾Hide ▴
Evidence considered
- Variant consequence is p.(Leu422TrpfsTer6).
- PS1 is unchanged from ACMG and applies to same amino acid substitutions.
Sources
PM3 N/APM3 is not applicable in this VCEP framework. Details ▾Hide ▴
PM4 N/APM4 is not applicable in this VCEP framework. Details ▾Hide ▴
PM5 N/APM5 applies to a novel missense change at an amino acid residue where a different missense pathogenic variant has been established. This variant is a frameshift, so PM5 is not applicable. Details ▾Hide ▴
PM6 N/APM6 is not applicable in this VCEP framework. Details ▾Hide ▴
PP1 N/APP1 is not applicable in this VCEP framework. Details ▾Hide ▴
PP2 N/APP2 applies to missense variants. This variant is a frameshift, so PP2 is not applicable. Details ▾Hide ▴
PP3 N/APP3 is not applicable in the Brain Malformations VCEP framework for PIK3CA gain-of-function interpretation, so computational pathogenicity prediction is not used to support pathogenicity here. Details ▾Hide ▴
Evidence considered
- VCEP marks PP3 as not applicable for this framework.
- SpliceAI max delta score is 0.07.
Sources
PP4 N/APP4 is not applicable in this VCEP framework because phenotype specificity is incorporated into the PS4 point-based system. Details ▾Hide ▴
PP5 N/APP5 is not applicable in this VCEP framework. Details ▾Hide ▴
BS4 N/ABS4 is not applicable in this VCEP framework because these disorders are interpreted in the context of de novo, germline mosaic, or post-zygotic variation rather than conventional lack-of-segregation evidence. Details ▾Hide ▴
BP1 N/ABP1 is not applicable in this VCEP framework. Details ▾Hide ▴
BP3 N/ABP3 is not applicable in this VCEP framework. Details ▾Hide ▴
BP4 N/ABP4 in this VCEP framework is limited to synonymous, non-canonical intronic, and UTR variants with no predicted splice effect. This variant is a frameshift, so BP4 is not applicable, although SpliceAI predicts no significant splice impact with a maximum delta score of 0.07. Details ▾Hide ▴
Evidence considered
- Variant consequence is frameshift.
- SpliceAI max delta score is 0.07.
Sources
BP6 N/ABP6 is not applicable in this VCEP framework. Details ▾Hide ▴
BP7 N/ABP7 applies to synonymous, non-canonical intronic, and UTR variants with low conservation and no predicted splice impact. This variant is a frameshift, so BP7 is not applicable. Details ▾Hide ▴
Evidence considered
- Variant consequence is frameshift.
- SpliceAI max delta score is 0.07.
Sources
Identifiers
- Gene
- PIK3CA
- Transcript
- NM_006218.4
- Coding (HGVS c.)
- NM_006218.4:c.1265del
- Protein (HGVS p.)
- NP_006209.2:p.(Leu422TrpfsTer6)
- GRCh38
- chr3:179210197 AT>A
- GRCh37
- chr3:178927985 AT>A
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 in the Brain Malformations VCEP framework for PIK3CA gain-of-function interpretation, so computational pathogenicity prediction is not used to support pathogenicity here. Details ▾Hide ▴
Evidence considered
- VCEP marks PP3 as not applicable for this framework.
- SpliceAI max delta score is 0.07.
Sources
BP4 N/ABP4 in this VCEP framework is limited to synonymous, non-canonical intronic, and UTR variants with no predicted splice effect. This variant is a frameshift, so BP4 is not applicable, although SpliceAI predicts no significant splice impact with a maximum delta score of 0.07. Details ▾Hide ▴
Evidence considered
- Variant consequence is frameshift.
- SpliceAI max delta score is 0.07.
Sources
BP7 N/ABP7 applies to synonymous, non-canonical intronic, and UTR variants with low conservation and no predicted splice impact. This variant is a frameshift, so BP7 is not applicable. Details ▾Hide ▴
Evidence considered
- Variant consequence is frameshift.
- SpliceAI max delta score is 0.07.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07).
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 ↗
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/?term=NM_006218.4%3Ac.1265del
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-178927985-AT-A?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-179210197-AT-A?dataset=g…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006218.4%3Ac.1265…
- OncoKB ↗www.oncokb.org/gene/PIK3CA/L422Wfs*6
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=108144181
- 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 = 0.07).
Functional
OncoKB oncogenicity for this specific variant: Unknown Oncogenic Effect (variant has not been individually curated).
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV104381249, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.