About PIK3R1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PIK3R1 c.1355A>G, p.(Tyr452Cys)
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. 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
The variant is extremely rare in gnomAD v4.1 (total allele frequency 6.47e-7, 1/1,544,610 alleles, 0 homozygotes), which is below the VCEP PM2_Supporting threshold of <0.00000132.
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 v1.0 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
1 / 1,544,610 alleles
gnomAD v4.1: 1 / 1,544,610 alleles. Recorded AF 6.47413e-07. Recorded homozygote count 0.
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
3 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV57130363, n = 3 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen PIK3R1 VCEP v1.0, with the data and sources behind each one.
27 criteria with recorded statuses: 1 met · 14 not met · 0 not assessed · 12 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.1355A>G (p.Tyr452Cys) in PIK3R1 is extremely rare in population databases (gnomAD v4.1 allele frequency 6.47e-7, 1 heterozygous allele among 1,544,610 alleles), meeting PM2_Supporting per Antibody Deficiencies VCEP specifications.
The variant is absent from ClinVar and has not been reported in any germline patient cohort, precluding assessment of PS4, PP1, PP4, or de novo criteria (PS2).
No functional data are available for this specific variant in any VCEP-approved assay (AKT kinase, lipid kinase, protein binding, conformational dynamics, knock-in mouse, or the PMID:40543502 screen); PS3 and BS3 cannot be assessed.
Computational predictors are indeterminate: REVEL 0.55 is intermediate between VCEP PP3 (≥0.644) and BP4 (≤0.290) thresholds, and SpliceAI predicts no splicing impact (max delta 0.00).
Under the Bayesian point-based framework adopted by the Antibody Deficiencies VCEP (≥10 = Pathogenic, 6-9 = Likely Pathogenic, 0-5 = VUS, -6 to -1 = Likely Benign, ≤-7 = Benign), the single PM2_Supporting assignment yields 1 point, classifying this variant as a Variant of Uncertain Significance.
No criteria match.
Met · 1
PM2 SupportingThe variant is extremely rare in gnomAD v4.1 (total allele frequency 6.47e-7, 1/1,544,610 alleles, 0 homozygotes), which is below the VCEP PM2_Supporting threshold of <0.00000132. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 total AF = 6.474e-7
- well below VCEP PM2_Supporting cutoff of 1.32e-6.
- Single heterozygous allele observed in 1
- 544
- 610 alleles
- no homozygotes.
- Maximum population AF is 8.89e-7 in European (non-Finnish).
Sources
Not met · 14 · evaluated, threshold not reached
PS1 No different missense variant at codon 452 (p.Tyr452) has been classified as Pathogenic or Likely Pathogenic by VCEP standards for PIK3R1. The variant is absent from ClinVar and no same-codon comparator exists. Details ▾Hide ▴
PS2 No de novo observation reported for this variant. The variant is absent from ClinVar and the sole literature source (PMID:29533785) is a somatic cancer functional screen containing no germline patient or de novo data. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no de novo submissions.
- PMID:29533785 is a cancer somatic mutation functional screen
- no germline de novo data for this variant.
Still missing
- No proband or de novo data available in any source.
Sources
PS3 NM_181523.2:c.1355A>G (p.Tyr452Cys) was not tested in any VCEP-approved functional assay. The VCEP spreadsheet confirms that none of the variant-specific approved assays (AKT kinase activity, lipid kinase activity, protein binding, conformational dynamics, knock-in mouse models, or the PMID:40543502 base-editing screen of 240 variants) include p.Tyr452Cys. Details ▾Hide ▴
Evidence considered
- VCEP-approved functional assays tested p.Arg649Trp
- c.1425+1G>T
- c.1425+1G>C
- p.Glu489Lys
- p.Tyr657Ter
- and 240 variants from PMID:40543502
- p.Tyr452Cys was not among them.
- PMID:29533785 performed systematic somatic variant screening but the variant is not individually reported and the paper is not a VCEP-approved assay.
Still missing
- No functional data of any kind for this specific variant.
Sources
cspec ↗vcep_04_08_26_pik3r1_functional_assays_ps3_bs3
PS4 No probands meeting VCEP phenotype scoring criteria have been reported for this variant. The variant is absent from ClinVar and not identified in any germline patient cohort. Details ▾Hide ▴
Evidence considered
- Variant is absent from ClinVar
- no patient observations.
- No probands available to score against VCEP PS4 phenotype rubric.
Still missing
- No clinical patient data for this variant.
Sources
PM5 No different missense variant at codon 452 classified as Pathogenic or Likely Pathogenic by VCEP standards. The PM5 candidate search found no comparators, and ClinVar has no entries for this variant or any other missense at codon 452. Details ▾Hide ▴
PP1 No co-segregation data available. No families with this variant have been reported in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no family studies.
- VCEP PP1 requires affected family members scoring ≥6 phenotype points on the PS4 rubric
- no such data exist.
Still missing
- No family or co-segregation data available.
Sources
PP3 REVEL score 0.55 is below the VCEP PP3 threshold of ≥0.644. SpliceAI max delta score 0.00 is below the ≥0.2 threshold. Neither computational path for PP3 is satisfied. Details ▾Hide ▴
Evidence considered
- REVEL = 0.55 (VCEP threshold for PP3 is ≥0.644
- not met).
- SpliceAI max delta = 0.00 (VCEP threshold for PP3 is ≥0.20
- BayesDel = 0.334 (not used by VCEP PP3 rules).
Sources
PP4 No proband meeting VCEP phenotype scoring criteria has been reported. The variant is absent from ClinVar, and no patient-specific phenotype or functional data are available to meet the VCEP PP4 rubric. Details ▾Hide ▴
Evidence considered
- No probands available for phenotype scoring.
- VCEP PP4 requires ≥10 phenotype points on PS4 rubric plus PIK3CD genotyping
- no patient data exist.
Still missing
- No patient phenotype data available.
Sources
BA1 Maximum population allele frequency in gnomAD v4.1 is 8.89e-7 (European non-Finnish), far below the VCEP BA1 threshold of ≥0.00316. Details ▾Hide ▴
Evidence considered
- Maximum population AF = 8.89e-7 (NFE)
- VCEP BA1 threshold is ≥0.00316.
Sources
BS1 Maximum population allele frequency in gnomAD v4.1 is 8.89e-7, below the VCEP BS1 threshold of ≥0.000316. Details ▾Hide ▴
Evidence considered
- Maximum population AF = 8.89e-7 (NFE)
- VCEP BS1 threshold is ≥0.000316.
Sources
BS3 No functional data demonstrating a non-damaging effect are available for this variant. The variant was not tested in any VCEP-approved functional assay (AKT kinase, lipid kinase, protein binding, conformational dynamics, knock-in mouse, or the PMID:40543502 screen). Details ▾Hide ▴
Evidence considered
- Not tested in any VCEP-approved BS3 functional assay.
- VCEP spreadsheet confirms no data for p.Tyr452Cys.
Still missing
- No benign functional data available for this variant.
Sources
cspec ↗vcep_04_08_26_pik3r1_functional_assays_ps3_bs3
BS4 No segregation data available. No families have been reported with this variant to assess lack of segregation with disease. Details ▾Hide ▴
Evidence considered
- No family data available.
- VCEP BS4 requires affected family members lacking the variant
- no such data exist.
Still missing
- No family or segregation data available.
Sources
BP4 REVEL score 0.55 exceeds the VCEP BP4 benign threshold of ≤0.290. Although SpliceAI max delta 0.00 is below the 0.1 threshold, both REVEL ≤0.290 and CADD ≤21.5 must be met; REVEL fails. Details ▾Hide ▴
Evidence considered
- REVEL = 0.55 (VCEP BP4 threshold is ≤0.290
- not met).
- SpliceAI max delta = 0.00 (<0.1 threshold met
- but both conditions required).
Sources
BP5 No cases with an alternative molecular basis for disease have been reported. VCEP requires at least 2 cases with alternative molecular diagnoses; none are available for this variant. Details ▾Hide ▴
Evidence considered
- VCEP requires ≥2 cases with alternative molecular basis
- no such data exist for this variant.
Still missing
- No alternative molecular diagnosis data available.
Sources
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable to missense variants under the Antibody Deficiencies VCEP for PIK3R1. This is a missense variant (NP_852664.1:p.Tyr452Cys) with SpliceAI max delta 0.00; VCEP PVS1 criteria are limited to nonsense/frameshift null variants, canonical splice variants, and missense variants with SpliceAI ≥0.2. Details ▾Hide ▴
Evidence considered
- Missense variant in exon 11
- SpliceAI max delta score 0.00 confirms no predicted splicing impact.
- VCEP PVS1 rules require a null variant type or SpliceAI ≥0.2 for missense variants
- neither applies.
Sources
PM1 VCEPPM1 is declared Not Applicable by the Antibody Deficiencies VCEP for PIK3R1. Details ▾Hide ▴
PM6 VCEPPM6 is declared Not Applicable by the Antibody Deficiencies VCEP; PS2 is used in lieu of PM6 for de novo observations. Details ▾Hide ▴
Evidence considered
- VCEP instructions: use PS2 instead of PM6 when de novo with unconfirmed parentage.
Sources
PP2 VCEPPP2 is declared Not Applicable by the Antibody Deficiencies VCEP for PIK3R1 (gnomAD missense Z-score 2.72 indicates the gene is not constrained for missense variation; both benign and pathogenic missense variants exist). Details ▾Hide ▴
Evidence considered
- VCEP explicitly not applicable: PIK3R1 gnomAD v2.1.1 missense Z = 2.72
- not constrained for missense variation.
Sources
PP5 VCEPPP5 is declared Not Applicable by the Antibody Deficiencies VCEP for PIK3R1. Additionally, the variant is absent from ClinVar, so no expert-panel pathogenic classification exists to cite. Details ▾Hide ▴
BS2 VCEPBS2 is declared Not Applicable by the Antibody Deficiencies VCEP due to incomplete penetrance and variable expressivity of PIK3R1-related disease. Details ▾Hide ▴
Evidence considered
- VCEP: BS2 does not apply due to incomplete penetrance and variable expressivity.
Sources
BP1 VCEPBP1 is declared Not Applicable by the Antibody Deficiencies VCEP because pathogenic PIK3R1 variants are not limited to truncating variants; missense variants can also be pathogenic. Details ▾Hide ▴
Evidence considered
- VCEP: BP1 not applicable
- pathogenic variants include missense
- not limited to truncating.
Sources
BP2 VCEPBP2 is declared Not Applicable by the Antibody Deficiencies VCEP because diverse combinatorial variant effects in PIK3R1 cannot be excluded. Details ▾Hide ▴
Evidence considered
- VCEP: BP2 not applicable
- diverse allelic mechanisms cannot be excluded for PIK3R1.
Sources
BP3 VCEPBP3 applies to in-frame deletions/insertions in repetitive regions; this is a missense substitution variant. Details ▾Hide ▴
Evidence considered
- Not an in-frame deletion/insertion.
BP6 VCEPBP6 is declared Not Applicable by the Antibody Deficiencies VCEP per ClinGen SVI VCEP Review Committee recommendation. Additionally, the variant is absent from ClinVar, providing no reputable benign classification to cite. Details ▾Hide ▴
BP7 N/ABP7 under the VCEP applies to synonymous and intronic variants not predicted to impact splicing. This is a missense variant (p.Tyr452Cys). Details ▾Hide ▴
Evidence considered
- VCEP BP7 criteria are specific to synonymous and intronic variants
- this is a missense substitution.
Sources
PS5 N/APS5 is not included in the Antibody Deficiencies VCEP framework for PIK3R1. Details ▾Hide ▴
Evidence considered
- PS5 is absent from the VCEP criteria set
- not part of the PIK3R1 specification.
Sources
Identifiers
- Gene
- PIK3R1
- Transcript
- NM_181523.2
- Coding (HGVS c.)
- NM_181523.2:c.1355A>G
- Protein (HGVS p.)
- NP_852664.1:p.(Tyr452Cys)
- GRCh38
- chr5:68293764 A>G
- GRCh37
- chr5:67589592 A>G
- COSMIC
- COSV57130363
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
1 / 1,544,610 alleles
AF 6.47e-07 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 6.5e-07 · 1 / 1,544,610 alleles · 0 hom
| European (non-Finnish)1 / 1,124,304 | 8.9e-07 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.47413e-07; MAF= 0.00006%, 1/1544610 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.89439e-07; MAF= 0.00009%, 1/1124304 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.550
- BayesDel
- 0.334
How the predictions were used
PP3 REVEL score 0.55 is below the VCEP PP3 threshold of ≥0.644. SpliceAI max delta score 0.00 is below the ≥0.2 threshold. Neither computational path for PP3 is satisfied. Details ▾Hide ▴
Evidence considered
- REVEL = 0.55 (VCEP threshold for PP3 is ≥0.644
- not met).
- SpliceAI max delta = 0.00 (VCEP threshold for PP3 is ≥0.20
- BayesDel = 0.334 (not used by VCEP PP3 rules).
Sources
BP4 REVEL score 0.55 exceeds the VCEP BP4 benign threshold of ≤0.290. Although SpliceAI max delta 0.00 is below the 0.1 threshold, both REVEL ≤0.290 and CADD ≤21.5 must be met; REVEL fails. Details ▾Hide ▴
Evidence considered
- REVEL = 0.55 (VCEP BP4 threshold is ≤0.290
- not met).
- SpliceAI max delta = 0.00 (<0.1 threshold met
- but both conditions required).
Sources
BP7 N/ABP7 under the VCEP applies to synonymous and intronic variants not predicted to impact splicing. This is a missense variant (p.Tyr452Cys). Details ▾Hide ▴
Evidence considered
- VCEP BP7 criteria are specific to synonymous and intronic variants
- this is a missense substitution.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.55. BayesDel score = 0.334045.
1 paper record 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 29533785 ↗Systematic Functional Annotation of Somatic Mutations in Cancer.Systematic functional annotation of over 1,000 somatic mutations across 95 cancer genes, including PIK3R1, using Ba/F3 and MCF10A cell viability assays. PIK3R1 is described as a gene with tumor suppressive properties; indel and nonsense mutations were included. NM_181523.2:c.1355A>G (p.Tyr452Cys) 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
1 / 1,544,610 recorded alleles
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.1355A%3EG
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/5-67589592-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr5-68293764-A-G?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/5-68293764-A-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_181523.2%3Ac.1355…
- OncoKB ↗www.oncokb.org/gene/PIK3R1/Y452C
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=185430278
- 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= 6.47413e-07; MAF= 0.00006%, 1/1544610 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.89439e-07; MAF= 0.00009%, 1/1124304 alleles, homozygotes = 0).
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). REVEL score = 0.55. BayesDel score = 0.334045.
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 lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV57130363, n = 3 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.