Variant classification summary

NM_181523.2:c.1355A>G

PIK3R1 · NP_852664.1:p.(Tyr452Cys) · NM_181523.2

GRCh37: chr5:67589592 A>G · GRCh38: chr5:68293764 A>G

Gene: PIK3R1 Transcript: NM_181523.2

Final call

VUS

PM2 supporting

Variant details

Gene

PIK3R1

Transcript

NM_181523.2

Protein

NP_852664.1:p.(Tyr452Cys)

gnomAD AF

6.474126154822252e-07 (v4.1)

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

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).

3

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.

4

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).

5

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.

Final determination: ClinGen Antibody Deficiencies Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PIK3R1 Version 1.0 v1.0 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	PVS1 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.	spliceai pvs1_variant_assessment cspec
PS1	Not met	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.	clinvar pm5_candidates cspec
PS2	Not met	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.	clinvar PMID:29533785
PS3	Not met	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.	cspec vcep_04_08_26_pik3r1_functional_assays_ps3_bs3
PS4	Not met	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.	clinvar
PS5	N/A	PS5 is not included in the Antibody Deficiencies VCEP framework for PIK3R1.	cspec
PM1	N/A	PM1 is declared Not Applicable by the Antibody Deficiencies VCEP for PIK3R1.	cspec
PM2	Met	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.	gnomad_v4 cspec
PM5	Not met	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.	clinvar pm5_candidates cspec
PM6	N/A	PM6 is declared Not Applicable by the Antibody Deficiencies VCEP; PS2 is used in lieu of PM6 for de novo observations.	cspec
PP1	Not met	No co-segregation data available. No families with this variant have been reported in ClinVar or the literature.	clinvar
PP2	N/A	PP2 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).	cspec
PP3	Not met	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.	revel spliceai cspec
PP4	Not met	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.	clinvar
PP5	N/A	PP5 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.	cspec clinvar
BA1	Not met	Maximum population allele frequency in gnomAD v4.1 is 8.89e-7 (European non-Finnish), far below the VCEP BA1 threshold of ≥0.00316.	gnomad_v4 cspec
BS1	Not met	Maximum population allele frequency in gnomAD v4.1 is 8.89e-7, below the VCEP BS1 threshold of ≥0.000316.	gnomad_v4 cspec
BS2	N/A	BS2 is declared Not Applicable by the Antibody Deficiencies VCEP due to incomplete penetrance and variable expressivity of PIK3R1-related disease.	cspec
BS3	Not met	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).	cspec vcep_04_08_26_pik3r1_functional_assays_ps3_bs3
BS4	Not met	No segregation data available. No families have been reported with this variant to assess lack of segregation with disease.	clinvar
BP1	N/A	BP1 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.	cspec
BP2	N/A	BP2 is declared Not Applicable by the Antibody Deficiencies VCEP because diverse combinatorial variant effects in PIK3R1 cannot be excluded.	cspec
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions; this is a missense substitution variant.
BP4	Not met	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.	revel spliceai cspec
BP5	Not met	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.	cspec
BP6	N/A	BP6 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.	cspec clinvar
BP7	N/A	BP7 under the VCEP applies to synonymous and intronic variants not predicted to impact splicing. This is a missense variant (p.Tyr452Cys).	cspec

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