About PIK3R1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PIK3R1 c.1345_1347del, p.(Leu449del)
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 PIK3R1 VCEP v1.0.0. 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
NM_181523.2:c.1345_1347del is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (total allele frequency = 0). This is below the VCEP PM2_Supporting threshold of <0.00000132, supporting pathogenicity.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
ClinGen Antibody Deficiencies Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PIK3R1 Version 1.0.0 v1.0.0 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.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
5 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV57127217, n = 5 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen PIK3R1 VCEP v1.0.0, with the data and sources behind each one.
28 criteria with recorded statuses: 1 met · 10 not met · 2 not assessed · 15 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_181523.2:c.1345_1347del (p.Leu449del) is an in-frame deletion of a single amino acid in exon 11 of PIK3R1, which encodes the p85-alpha regulatory subunit of PI3K. The variant has not been reported in ClinVar and is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2_Supporting under the Antibody Deficiencies VCEP framework (total AF = 0; threshold <0.00000132).
The variant has been observed in somatic cancers (COSMIC COSV57127217, n=5) and is annotated as Likely Oncogenic / Likely Loss-of-function by OncoKB. However, no variant-specific germline functional data are available from VCEP-approved assays (lipid kinase activity, AKT kinase activity, protein binding, conformational dynamics, mouse knock-in, or pS6/pAKT T-cell enrichment assay). PS3 and BS3 are not met.
PVS1, PS1, PM1, PM5, PM6, PP2, PP5, BS2, BP1, BP2, BP3, BP6, and BP7 are not applicable under the Antibody Deficiencies VCEP specifications. PM4 is not met because the deletion removes only one amino acid (threshold: >=2 amino acids). PP3 and BP4 do not apply to in-frame deletions under current VCEP rules. BA1 and BS1 are not met as the variant is absent from population databases.
PS2, PS4, PP1, PP4, BS4, and BP5 cannot be assessed due to absence of proband phenotype data, family segregation studies, and alternative molecular diagnoses in the available literature and case materials.
Applying the PIK3R1 VCEP Bayesian point-based classification framework (Tavtigian 2020 adaptation): the only met criterion is PM2_Supporting (+1 point). Total = 1 point, which falls in the VUS range (0-5 points). The evidence is insufficient to classify this variant as pathogenic or benign at this time.
No criteria match.
Met · 1
PM2 SupportingNM_181523.2:c.1345_1347del is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (total allele frequency = 0). This is below the VCEP PM2_Supporting threshold of <0.00000132, supporting pathogenicity. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (0 alleles)
- gnomAD v4.1 (0 alleles)
- and gnomAD-Canada (0 alleles). Total AF = 0
- which is below the VCEP PM2_Supporting threshold of 0.00000132.
Sources
Not met · 10 · evaluated, threshold not reached
PS3 The variant is not included in any VCEP-approved functional assay dataset. The Antibody Deficiencies VCEP xlsx (04_08_26_PIK3R1_Functional_Assays_PS3_BS3.xlsx) lists variants tested across lipid kinase, AKT kinase, protein binding, conformational dynamics, mouse knock-in, and splicing assays — NM_181523.2:c.1345_1347del is absent from all. OncoKB annotation of Likely Oncogenic / Likely Loss-of-function represents somatic cancer curation and does not constitute germline functional evidence under VCEP-approved assay standards. Details ▾Hide ▴
PS4 No probands with PIK3R1-related immunodeficiency harboring NM_181523.2:c.1345_1347del have been identified in the literature or case materials. No proband meets the VCEP PS4 phenotype scoring criteria (Table 3). The variant is absent from ClinVar, and the two literature PMIDs are cancer-focused studies that do not describe germline immunodeficiency probands. Details ▾Hide ▴
PM4 The VCEP PM4 criterion requires an in-frame deletion resulting in a protein length change of >= 2 amino acids with at least one deleted nucleotide having a PhyloP score >= 2.0. NM_181523.2:c.1345_1347del results in deletion of a single amino acid (p.Leu449del), which does not meet the >= 2 amino acid threshold. Details ▾Hide ▴
Evidence considered
- In-frame deletion of 1 amino acid (p.Leu449del) does not meet the VCEP PM4 threshold of >= 2 amino acid protein length change.
Sources
PP3 The VCEP PP3 criterion for missense variants requires REVEL >= 0.644 and CADD >= 26.0. Neither score is available for this in-frame deletion. PP3 for splicing impact requires a SpliceAI delta score >= 0.2. SpliceAI predicts no significant splice impact (max delta = 0.00). Details ▾Hide ▴
Evidence considered
- REVEL not applicable (not SNV)
- SpliceAI max delta = 0.00
- below VCEP PP3 threshold of 0.20.
Sources
PP4 No proband with NM_181523.2:c.1345_1347del meets the VCEP PP4 phenotype scoring criteria (>=10 points on PS4 counting rubric with genotyping ruling out PIK3CD alterations). No proband-level clinical data are available in the literature or case materials. Details ▾Hide ▴
Evidence considered
- No proband phenotype data available.
Still missing
- No proband with detailed phenotype and PIK3CD genotyping available.
Sources
BA1 NM_181523.2:c.1345_1347del is absent from gnomAD v4.1 (allele frequency = 0). The VCEP BA1 threshold requires a GrpMax filtering allele frequency >= 0.00316. The variant's population frequency is far below this threshold. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v4.1 (AF = 0)
- does not meet VCEP BA1 threshold of >= 0.00316.
Sources
BS1 NM_181523.2:c.1345_1347del is absent from gnomAD v4.1 (allele frequency = 0). The VCEP BS1 threshold requires a GrpMax filtering allele frequency >= 0.000316. The variant's population frequency is far below this threshold. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v4.1 (AF = 0)
- does not meet VCEP BS1 threshold of >= 0.000316.
Sources
BS3 The variant is not included in any VCEP-approved functional assay. The Antibody Deficiencies VCEP xlsx lists all variants tested in approved assay classes (lipid kinase activity, AKT kinase activity, protein binding, conformational dynamics, mouse knock-in, pS6/pAKT T-cell enrichment assay) — NM_181523.2:c.1345_1347del is absent from all. No variant-specific functional data supporting a benign effect are available. Details ▾Hide ▴
Evidence considered
- Variant absent from all VCEP-approved functional assay datasets. No non-damaging functional data available.
Sources
BS4 No family segregation data are available to demonstrate lack of co-segregation with PIK3R1-related immunodeficiency. No affected family members lacking NM_181523.2:c.1345_1347del have been reported. Details ▾Hide ▴
Still missing
- No segregation data available.
Sources
2848135929636360
BP5 The VCEP BP5 criterion requires at least 2 cases with an alternative molecular basis for disease. No such cases have been identified for NM_181523.2:c.1345_1347del in the literature or case materials. Details ▾Hide ▴
Evidence considered
- No cases with alternative molecular basis identified.
Still missing
- No cases with alternative molecular diagnosis available.
Sources
Not assessed · 2 · no assessment recorded
PS2 No de novo occurrence data are available for NM_181523.2:c.1345_1347del in any proband with PIK3R1-related immunodeficiency. The literature and case materials do not contain de novo segregation reports for this variant. Details ▾Hide ▴
Still missing
- De novo status has not been assessed — no proband or parental genotype data available.
Sources
2848135929636360
PP1 No co-segregation data are available for NM_181523.2:c.1345_1347del. The literature and case materials contain no family studies with this variant. Details ▾Hide ▴
Still missing
- No family co-segregation data available.
Sources
2848135929636360
Not applicable · 15· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_181523.2:c.1345_1347del is an in-frame deletion of a single amino acid (p.Leu449del). The Antibody Deficiencies VCEP PVS1 rules are defined for nonsense/frameshift variants introducing premature termination codons, canonical splice-site variants, and select missense/synonymous/intronic variants with SpliceAI-predicted splicing effects. An in-frame single amino acid deletion does not qualify for PVS1 under this framework. Details ▾Hide ▴
Evidence considered
- In-frame single amino acid deletion (p.Leu449del) does not fall into any VCEP-defined PVS1 variant class (nonsense
- frameshift
- or canonical splice). SpliceAI max delta = 0.00 confirms no cryptic splice impact.
Sources
PS1 N/AThe VCEP PS1 criterion applies exclusively to missense variants and canonical splice variants. NM_181523.2:c.1345_1347del is an in-frame deletion and does not meet PS1 eligibility criteria. Details ▾Hide ▴
Evidence considered
- In-frame deletion is not a missense or splice variant
- VCEP PS1 rules do not apply to this variant class.
Sources
PM1 VCEPThe Antibody Deficiencies VCEP explicitly designates PM1 as Not Applicable for PIK3R1. Details ▾Hide ▴
PM5 N/AThe VCEP PM5 criterion applies exclusively to missense variants with a different pathogenic/likely pathogenic missense change at the same codon. NM_181523.2:c.1345_1347del is an in-frame deletion, not a missense variant. Details ▾Hide ▴
Evidence considered
- Variant class is in-frame deletion
- not missense. PM5 is limited to missense comparator variants at the same codon.
Sources
cspec ↗pm5_candidates
PM6 VCEPThe Antibody Deficiencies VCEP explicitly designates PM6 as Not Applicable, directing use of PS2 for apparent de novo scenarios. Details ▾Hide ▴
PP2 VCEPThe Antibody Deficiencies VCEP explicitly designates PP2 as Not Applicable for PIK3R1. The gnomAD missense Z-score (2.72) does not indicate constraint, and both benign and pathogenic missense variants are known in this gene. Details ▾Hide ▴
PP5 VCEPThe Antibody Deficiencies VCEP explicitly designates PP5 as Not Applicable for use, per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. Details ▾Hide ▴
BS2 VCEPThe Antibody Deficiencies VCEP explicitly designates BS2 as Not Applicable, due to incomplete penetrance and variable expressivity of PIK3R1-related disease. Details ▾Hide ▴
BP1 VCEPThe Antibody Deficiencies VCEP explicitly designates BP1 as Not Applicable. Pathogenic PIK3R1 variants are not limited to truncating variants and include missense changes. Details ▾Hide ▴
BP2 VCEPThe Antibody Deficiencies VCEP explicitly designates BP2 as Not Applicable. The full spectrum of allelic mechanisms for PIK3R1 variants is not yet understood, precluding use of this criterion. Details ▾Hide ▴
BP3 VCEPThe Antibody Deficiencies VCEP explicitly designates BP3 as Not Applicable. Details ▾Hide ▴
BP4 N/AThe VCEP BP4 criterion is defined for missense variants (REVEL <= 0.290 and CADD <= 21.5 with SpliceAI < 0.1) and for synonymous/intronic variants (SpliceAI < 0.1). NM_181523.2:c.1345_1347del is an in-frame deletion, which falls outside the variant classes addressed by VCEP BP4 rules. Details ▾Hide ▴
Evidence considered
- In-frame deletion not addressed by VCEP BP4 rules (which cover only missense and synonymous/intronic variants). SpliceAI max delta = 0.00
- but no applicable BP4 rule for this variant class.
Sources
BP6 VCEPThe Antibody Deficiencies VCEP explicitly designates BP6 as Not Applicable, per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. Details ▾Hide ▴
BP7 N/AThe VCEP BP7 criterion applies to synonymous variants (outside first/last 3 nucleotides of exon) and intronic variants (outside +1 to +6 and -1 to -20 positions) with no predicted splice impact by SpliceAI. NM_181523.2:c.1345_1347del is an in-frame deletion and does not fit either variant class. Details ▾Hide ▴
Evidence considered
- In-frame deletion not addressed by VCEP BP7 (synonymous or intronic variants only). SpliceAI max delta = 0.00
- but no applicable BP7 rule for this variant class.
Sources
PS5 N/APS5 is not a standard ACMG/AMP criterion and is not defined in the Antibody Deficiencies VCEP specifications for PIK3R1. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- PIK3R1
- Transcript
- NM_181523.2
- Coding (HGVS c.)
- NM_181523.2:c.1345_1347del
- Protein (HGVS p.)
- NP_852664.1:p.(Leu449del)
- GRCh38
- chr5:68293752 AATT>A
- GRCh37
- chr5:67589580 AATT>A
- COSMIC
- COSV57127217
Gene diagram
Every interpreted variant in PIK3R1, mapped onto the exon structure of NM_181523.2. Select a row to find it on the plot.
PIK3R1NM_181523.2
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 PIK3R1
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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
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 The VCEP PP3 criterion for missense variants requires REVEL >= 0.644 and CADD >= 26.0. Neither score is available for this in-frame deletion. PP3 for splicing impact requires a SpliceAI delta score >= 0.2. SpliceAI predicts no significant splice impact (max delta = 0.00). Details ▾Hide ▴
Evidence considered
- REVEL not applicable (not SNV)
- SpliceAI max delta = 0.00
- below VCEP PP3 threshold of 0.20.
Sources
BP4 N/AThe VCEP BP4 criterion is defined for missense variants (REVEL <= 0.290 and CADD <= 21.5 with SpliceAI < 0.1) and for synonymous/intronic variants (SpliceAI < 0.1). NM_181523.2:c.1345_1347del is an in-frame deletion, which falls outside the variant classes addressed by VCEP BP4 rules. Details ▾Hide ▴
Evidence considered
- In-frame deletion not addressed by VCEP BP4 rules (which cover only missense and synonymous/intronic variants). SpliceAI max delta = 0.00
- but no applicable BP4 rule for this variant class.
Sources
BP7 N/AThe VCEP BP7 criterion applies to synonymous variants (outside first/last 3 nucleotides of exon) and intronic variants (outside +1 to +6 and -1 to -20 positions) with no predicted splice impact by SpliceAI. NM_181523.2:c.1345_1347del is an in-frame deletion and does not fit either variant class. Details ▾Hide ▴
Evidence considered
- In-frame deletion not addressed by VCEP BP7 (synonymous or intronic variants only). SpliceAI max delta = 0.00
- but no applicable BP7 rule for this variant class.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
2 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 28481359 ↗Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients.Reports the mutational landscape from prospective clinical sequencing of >10,000 advanced cancer patients using the MSK-IMPACT assay. NM_181523.2:c.1345_1347del (p.Leu449del) was not identified as a germline variant associated with PIK3R1-related immunodeficiency in this cohort.Does not name this variant
-
PMID 29636360 ↗A First-in-Human Phase 1 Study of LY3023414, an Oral PI3K/mTOR Dual Inhibitor, in Patients with Advanced Cancer.Phase 1 dose-escalation study of LY3023414, an oral PI3K/mTOR dual inhibitor, in 47 patients with advanced solid tumors. NM_181523.2:c.1345_1347del (p.Leu449del) was not identified in this paper.Does not name this variant
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
Recorded maximum delta 0.000
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/1626566541
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_181523.2%3Ac.1345_1347delTTA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/5-67589580-AATT-A?dataset=gno…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr5-68293752-AATT-A?dataset=…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/5-68293752-AATT-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_181523.2%3Ac.1345…
- OncoKB ↗www.oncokb.org/gene/PIK3R1/L449del
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=185425282
- 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.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV57127217, n = 5 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.