Classification rationale

PM2 VUS

PIK3CA c.946C>T

PM2 (Supporting): variant absent from gnomAD v2.1, v4.1, and gnomAD-Canada (0 alleles, within the <=1 occurrence ceiling). Overall classification: Variant of Uncertain Significance, because the single supporting PM2 criterion satisfies no benign or pathogenic combination threshold.

PM2 → VUS

Gene diagram · NM_006218.3 · variants mapped to exon structure

PIK3CA NM_006218.3

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 13 assessed

Applied · 1

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

Met (Supporting): 0 alleles across gnomAD v2.1, v4.1, and gnomAD-Canada, within the <=1 occurrence ceiling.

gnomAD v2.1 variant page: 3-178921464-C-T absent, 0 alleles (evidence.json GNOMAD_V2_1 search_status=absent)gnomAD v4.1 variant page: chr3-179203676-C-T absent, 0 alleles (evidence.json GNOMAD_V4_1 search_status=absent)gnomAD-Canada v1.0 API: 3-179203676-C-T absent, 0 alleles (evidence.json GNOMAD_CANADA_V1 search_status=absent)

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗cspec ↗

Assessed · not applied

Pathogenic

PS1 Not met: no established pathogenic p.Pro316Ser change arising from a different nucleotide is on record.

PS2 Not assessed: no parental or multi-tissue testing data were available to evaluate de novo occurrence.

PS3 Not assessed: insufficient functional-study evidence was available.

PS4 Not assessed: no affected individuals carrying this variant are reported, so no case phenotype points could be scored.

PM1 Not met: p.Pro316 lies outside the VCEP-approved kinase domains (amino acids 322-483 and 797-1068).

PM5 Not met: no alternate missense change at Pro316 with a pathogenic classification was identified.

PP2 Not assessed: the PIK3CA missense constraint z-score was unavailable, so the >3.09 rule could not be evaluated.

Benign

BA1 Not met: observed allele frequency 0, far below the 0.0926% BA1 threshold.

BS1 Not met: observed allele frequency 0, below the 0.0185% BS1 threshold.

BS2 Not met: zero homozygotes in gnomAD (threshold >=3) and no family-member observations.

BS3 Not assessed: no functional study evidence was available to evaluate.

BP2 Not met: no documented co-occurrence in cis or trans with a known pathogenic PIK3CA variant.

BP5 Not assessed: no case-level data were available on an alternate molecular basis of disease.

N/A · 14 PVS1 · PM3 · PM4 · PM6 · PP1 · PP3 · PP4 · PP5 · BS4 · BP1 · BP3 · BP4 · BP6 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

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 = 0.02). REVEL score = 0.115. BayesDel score = -0.369414.

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. PIK3CA, the catalytic subunit of PI3-kinase, is frequently mutated in a diverse range of cancers including breast, endometrial and cervical 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 not previously been reported in somatic cancers (COSMIC).

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