Classification rationale

PM2 VUS

STAG2 c.2431G>T nonsense · exon 25

PM2 (Supporting): variant absent from gnomAD v2.1, v4.1 (~800K alleles), and gnomAD-Canada v1.0 (AF = 0). VUS: the single supporting criterion (PM2) satisfies no combination rule in the generic ACMG/AMP 2015 fallback.

PM2 → VUS

Gene diagram · NM_001042749.1 · variants mapped to exon structure

STAG2 NM_001042749.1

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 19 assessed

Applied · 1

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

Met (supporting): absent from gnomAD v2.1, v4.1 (~800,000 alleles), and gnomAD-Canada v1.0.

Variant is absent from gnomAD v2.1 (X-123205071-G-T), gnomAD v4.1 (chrX-124071221-G-T), and gnomAD-Canada v1.0 (search_status 'absent' in all three), satisfying PM2 'absent in large population cohorts' (Richards et al. 2015, PMID 25741868).Absence across the gnomAD v4.1 cohort (~800K alleles) and gnomAD v2.1 is far below this lab's non-VCEP PM2 operating threshold of AF <0.1%.STAG2 has strong germline loss-of-function disease context (pvs1_gene_context), and extreme rarity in population databases is the expectation for a pathogenic X-linked LoF variant; PM2 is applied at supporting strength only (PM2_supporting) consistent with ClinGen SVI recommendations, rather than the moderate strength listed in the original 2015 framework.

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Assessed · not applied

Pathogenic

PVS1 Not assessed: insufficient evidence was available to evaluate a predicted loss-of-function effect.

PS2 Not assessed: no proband clinical data or parental-genotype confirmation exist to evaluate a de novo origin.

PS3 Not assessed: no well-established functional assay of this exact variant was available.

PS4 Not met: no case-control enrichment data exist; the variant is absent from ClinVar, gnomAD, and COSMIC.

PM3 Not assessed: no phase or biallelic observations in affected individuals are available.

PM6 Not assessed: no proband observation or parental testing exists to support an assumed de novo origin.

PP1 Not assessed: no family members are genotyped, so no meioses are available to score segregation.

PP3 Not met: SpliceAI max delta 0.033 is far below the >0.2 splice-altering threshold.

PP4 Not assessed: no proband phenotype or family-history data are available to evaluate phenotype specificity.

PP5 Not met: the variant has no ClinVar record, so no expert-panel pathogenic classification exists to trigger PP5.

Benign

BA1 Not met: allele frequency is 0 in gnomAD, far below the >5% BA1 threshold.

BS1 Not met: absent from gnomAD (AF 0), below the >0.3% expected-frequency threshold.

BS2 Not met: no observations in healthy adults exist, the opposite of what BS2 requires.

BS3 Not assessed: no functional study demonstrates retained STAG2 function or normal splicing.

BS4 Not assessed: no family members are genotyped, so non-segregation cannot be documented.

BP2 Not assessed: no second variant is observed in cis or trans, and no phase information exists.

BP4 Not met: the stop-gain itself is an impact on the gene product; SpliceAI (0.033) does not negate it.

BP5 Not assessed: no proband-level data exist to determine an alternate molecular basis of disease.

BP6 Not met: the variant has no ClinVar record, so no expert-panel benign classification exists to trigger BP6.

N/A · 8 PS1 · PM1 · PM4 · PM5 · PP2 · BP1 · BP3 · 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 = 0.03). BayesDel score = 0.652534.

SpliceAI ↗

Functional Likely Oncogenic

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

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

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 4 PMIDs not cited in assessment

21852505 ↗ Mutational inactivation of STAG2 causes aneuploidy in human cancer. ONCOKB

22417201 ↗ Clonal architecture of secondary acute myeloid leukemia. ONCOKB

24121789 ↗ Frequent truncating mutations of STAG2 in bladder cancer. ONCOKB

25010205 ↗ The genomic landscape of the Ewing Sarcoma family of tumors reveals recurrent STAG2 mutation. ONCOKB