Classification rationale

PM2 VUS

PIK3R1 c.1585_1587del

NM_181523.2:c.1585_1587del (p.Asp529del) is absent from all gnomAD population databases, fulfilling VCEP PM2_Supporting (AF < 0.00000132).¹ No other pathogenic or benign criteria were met under the Antibody Deficiencies VCEP specifications for PIK3R1. The variant is an in-frame deletion of a single amino acid in exon 13 (iSH2 domain) and is not predicted to alter splicing (SpliceAI max delta = 0.00).² With a single supporting-level pathogenic criterion (PM2_Supporting = +1 Bayesian point), the variant falls in the Uncertain Significance range (0-5 points) under the Tavtigian 2020 Bayesian point scale adopted by the VCEP.³

PM2 → VUS

1 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

2 cspec ↗spliceai ↗

3 final_classification_framework

Gene diagram · NM_181523.2 · variants mapped to exon structure

PIK3R1 NM_181523.2

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 14 assessed

Applied · 1

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

NM_181523.2:c.1585_1587del (p.Asp529del) is absent from all gnomAD population databases (v2.1, v4.1, Canada), satisfying the VCEP PM2_Supporting threshold of total allele frequency < 0.00000132 across all populations.

Absent from gnomAD v2.1 (exomes)Absent from gnomAD v4.1 (exomes)Absent from gnomAD-Canada v1.0 (genomes)

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Assessed · not applied

Pathogenic

PS2 No de novo observation with confirmed maternity and paternity has been reported for this variant.

PS3 No functional studies directly testing NM_181523.2:c.1585_1587del (p.Asp529del) were identified in the literature or in the VCEP-approved functional assay compendium (04_08_26_PIK3R1_Functional_Assays_PS3_BS3.xlsx).

PS4 No probands with this variant meeting the VCEP PS4 phenotype scoring criteria (≥6 points) and PIK3CD genotyping requirements have been identified in the available evidence.

PM4 VCEP PM4 requires an in-frame deletion resulting in a protein length change of ≥2 amino acids.

PP1 No co-segregation data is available for this variant.

PP3 VCEP PP3 criteria are: (1) missense variant with REVEL ≥0.644 and CADD ≥26.0 — not applicable for this in-frame deletion; (2) missense, synonymous, or intronic variants with SpliceAI Δ ≥0.2 — not applicable as this is an in-frame deletion, and SpliceAI max delta is 0.00 anyway.

PP4 No proband phenotype data meeting the VCEP PP4 threshold (≥10 phenotype points with PIK3CD genotyping) is available for this variant.

Benign

BA1 Variant is absent from gnomAD (v2.1, v4.1, Canada).

BS1 Variant is absent from gnomAD (v2.1, v4.1, Canada).

BS3 No functional studies showing a non-damaging effect for p.Asp529del were identified.

BS4 No segregation data showing affected family members lacking the variant is available.

BP4 VCEP BP4 is met by: (1) missense variants with REVEL ≤0.290 and CADD ≤21.5 and all SpliceAI Δ <0.1, or (2) synonymous/intronic variants without splice impact.

BP5 No cases with an alternative molecular basis for disease have been identified for this variant.

BP7 VCEP BP7 applies to synonymous variants (except first/last 3 nucleotides of exon) or intronic variants (outside +1 to +6 and -1 to -20 positions) without splice impact.

N/A · 12 PVS1 · PS1 · PM1 · PM5 · PM6 · PP2 · PP5 · BS2 · BP1 · BP2 · BP3 · BP6

Research & evidence

Population frequency

v4.1

This variant is absent from gnomAD v4.1.

v2.1

This variant is absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PIK3R1, the regulatory subunit of PI3-kinase, is mutated in various cancers, most frequently in glioma, endometrial and colorectal cancers.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV109582795, n = 1 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots