Variant classification summary

NM_181523.2:c.1345_1347delTTA

PIK3R1 · NP_852664.1:p.(Leu449del) · NM_181523.2

GRCh37: chr5:67589580 AATT>A · GRCh38: chr5:68293752 AATT>A

Gene: PIK3R1 Transcript: NM_181523.2

Final call

VUS

PM2 supporting

Variant details

Gene

PIK3R1

Transcript

NM_181523.2

Protein

NP_852664.1:p.(Leu449del)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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).

2

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.

3

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.

4

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.

5

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.

Final determination: 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 yields a total score of 1, which maps to VUS under the specified Tavtigian-style ranges.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	NM_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.	cspec
PS1	N/A	The 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.	cspec
PS2	Not assessed	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.
PS3	Not met	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.	cspec vcep_04_08_26_pik3r1_functional_assays_ps3_bs3 oncokb
PS4	Not met	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.	cspec clinvar
PS5	N/A	PS5 is not a standard ACMG/AMP criterion and is not defined in the Antibody Deficiencies VCEP specifications for PIK3R1.
PM1	N/A	The Antibody Deficiencies VCEP explicitly designates PM1 as Not Applicable for PIK3R1.	cspec
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada cspec
PM4	Not met	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.	cspec
PM5	N/A	The 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.	cspec pm5_candidates
PM6	N/A	The Antibody Deficiencies VCEP explicitly designates PM6 as Not Applicable, directing use of PS2 for apparent de novo scenarios.	cspec
PP1	Not assessed	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.
PP2	N/A	The 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.	cspec
PP3	Not met	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).	cspec spliceai
PP4	Not met	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.	cspec
PP5	N/A	The Antibody Deficiencies VCEP explicitly designates PP5 as Not Applicable for use, per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation.	cspec
BA1	Not met	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.	gnomad_v4 cspec
BS1	Not met	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.	gnomad_v4 cspec
BS2	N/A	The Antibody Deficiencies VCEP explicitly designates BS2 as Not Applicable, due to incomplete penetrance and variable expressivity of PIK3R1-related disease.	cspec
BS3	Not met	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.	cspec vcep_04_08_26_pik3r1_functional_assays_ps3_bs3
BS4	Not met	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.
BP1	N/A	The Antibody Deficiencies VCEP explicitly designates BP1 as Not Applicable. Pathogenic PIK3R1 variants are not limited to truncating variants and include missense changes.	cspec
BP2	N/A	The 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.	cspec
BP3	N/A	The Antibody Deficiencies VCEP explicitly designates BP3 as Not Applicable.	cspec
BP4	N/A	The 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.	cspec spliceai
BP5	Not met	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.	cspec
BP6	N/A	The Antibody Deficiencies VCEP explicitly designates BP6 as Not Applicable, per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation.	cspec
BP7	N/A	The 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.	cspec spliceai

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