Variant classification summary

NM_181523.2:c.1126G>A

PIK3R1 · NP_852664.1:p.(Gly376Arg) · NM_181523.2

GRCh37: chr5:67589138 G>A · GRCh38: chr5:68293310 G>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.(Gly376Arg)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): absent from gnomAD v4.1, total allele frequency below the VCEP's 0.00000132 threshold.

2

Overall classification VUS: point total +1 under the Bayesian framework (Rule3: 0–5 points).

Final determination: Under the PIK3R1 VCEP point-based framework, a total evidence score of 0-5 (Rule3) maps to Uncertain Significance; this variant scores +1 from PM2_Supporting alone, with no other criteria met.

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	Not applicable: this is a missense substitution, and the PIK3R1 VCEP PVS1 rule covers only loss-of-function variants.	cspec
PS1	Not assessed	Not assessed: no alternate-nucleotide variant producing the same p.(Gly376Arg) change with a pathogenic VCEP classification was identified.	cspec pm5_candidates
PS2	Not assessed	Not assessed: no parental genotypes, parentage confirmation, or family-history information was available to establish a de novo occurrence.	cspec
PS3	Not assessed	Not assessed: no data showed this variant tested in the VCEP-approved functional assays (lipid/AKT kinase, protein binding, conformational dynamics).
PS4	Not assessed	Not assessed: no germline immunodeficiency probands with this variant and evaluable phenotype data were available.	cspec clinvar
PM1	N/A	Not applicable: the PIK3R1 VCEP specification designates PM1 out of scope, with no hotspot-based moderate criterion for missense variants.	cspec
PM2	Met	Met (Supporting): absent from gnomAD v4.1, total allele frequency below the VCEP's 0.00000132 threshold.	cspec gnomad_v4
PM3	N/A	Not applicable: the PIK3R1 VCEP limits PM3 to recessive disorders, and the curated disease context here is autosomal dominant.	cspec
PM4	N/A	Not applicable: a single-nucleotide missense change alters one amino acid without changing protein length, so the in-frame-indel/stop-loss rule does not apply.	cspec
PM5	Not assessed	Not assessed: no different-amino-acid change at codon 376 with a pathogenic VCEP classification was available to compare.	cspec pm5_candidates
PM6	N/A	Not applicable: the VCEP handles de novo evidence through PS2 instead, and no parental-testing data were available.	cspec
PP1	Not assessed	Not assessed: no relatives' genotypes, phenotypes, or meioses were documented, so co-segregation could not be counted.	cspec
PP2	N/A	Not applicable: the PIK3R1 VCEP specification designates PP2 out of scope for this gene.	cspec
PP3	Not assessed	Not assessed: REVEL 0.778 clears the 0.644 threshold, but the required CADD score was unavailable, so the PP3 missense condition could not be confirmed.	cspec revel spliceai
PP4	Not assessed	Not assessed: no individual with the germline PIK3R1-related phenotype was documented, so phenotype score and PIK3CD exclusion could not be evaluated.	cspec clinvar
PP5	Not assessed	Not assessed: no ClinVar expert-panel pathogenic or likely-pathogenic classification exists for this exact variant.	clinvar
BA1	Not met	Not met: absent from gnomAD v4.1, below the VCEP's 0.00316 GrpMax allele-frequency threshold.	cspec gnomad_v4
BS1	Not met	Not met: absent from gnomAD v4.1, below the VCEP's 0.000316 GrpMax allele-frequency threshold.	cspec gnomad_v4
BS2	N/A	Not applicable: the PIK3R1 VCEP specification designates BS2 out of scope.	cspec
BS3	Not assessed	Not assessed: no functional assay data specific to this variant were available, so a benign assay result could not be confirmed.
BS4	Not assessed	Not assessed: no affected relatives reported as lacking this variant were documented, so non-segregation could not be assessed.	cspec
BP1	N/A	Not applicable: the PIK3R1 VCEP specification designates BP1 out of scope.	cspec
BP2	N/A	Not applicable: the PIK3R1 VCEP disallows BP2 because allelic mechanisms and combinatorial variant effects are not fully understood.	cspec
BP3	N/A	Not applicable: the PIK3R1 VCEP specification marks BP3 out of scope for this gene.	cspec
BP4	Not met	Not met: REVEL 0.778 far exceeds the ≤0.290 ceiling, so the BP4 missense condition fails outright.	cspec revel
BP5	Not assessed	Not assessed: no evidence showed this variant in an individual with an independently established alternative molecular cause.	cspec clinvar
BP6	Not assessed	Not assessed: no ClinVar expert-panel benign or likely-benign classification exists for this exact variant.	clinvar
BP7	N/A	Not applicable: the VCEP's BP7 applies only to synonymous or intronic variants, not this missense change.	cspec

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.