Classification rationale

PM2 BP4 VUS

STAG2 c.488T>A

NM_001042749.1:c.488T>A (p.Met163Lys) in STAG2 is a missense variant absent from population databases (PM2_Supporting).¹ Multiple in silico predictors (BayesDel = -0.143, SpliceAI max delta = 0.01) suggest no significant impact on protein function or splicing (BP4_Supporting).² This variant is absent from ClinVar, has no published functional data, and has not been reported in any disease cohort. The variant is not a null variant type (PVS1 not met) and does not reside in a mutational hotspot (PM1 not met).³ With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is balanced and insufficient for classification beyond a variant of uncertain significance (VUS).⁴

PM2 + BP4 → VUS

1 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

2 bayesdelspliceai ↗

3 clinvar ↗oncokb ↗

4 generic_acmg_combination_rules

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

STAG2 NM_001042749.1

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 22 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

NM_001042749.1:c.488T>A is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 (allele count = 0 in all datasets). The variant has not been observed in population reference databases, meeting the PM2 threshold for a rare variant (allele frequency <0.1%).

gnomAD v2.1: absent (AC=0)gnomAD v4.1: absent (AC=0)gnomAD-Canada v1.0: absent (AC=0

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

BP4 supporting Benign

Multiple lines of computational evidence predict no significant impact on the gene product. BayesDel score is -0.143023 (benign), and SpliceAI predicts no splicing effect (max delta score = 0.01). Two independent in silico predictors agree on a neutral/benign effect, meeting BP4 at supporting strength.

BayesDel: -0.143023 (benign prediction)SpliceAI: max delta 0.01 (no splice alteration predicted)

spliceai ↗

Assessed · not applied

Pathogenic

PVS1 NM_001042749.1:c.488T>A is a missense variant (p.Met163Lys) and does not fall into the ClinGen PVS1 null-variant categories of nonsense, frameshift, or canonical ±1,2 splice consensus variants.

PS1 No pathogenic or likely pathogenic variant with the same amino acid change (p.Met163Lys) has been reported in ClinVar or the literature.

PS2 No de novo data are available for this variant.

PS3 No functional studies have tested NM_001042749.1:c.488T>A or a systematically characterized range that includes p.Met163.

PS4 No case-control or patient cohort prevalence data are available for this variant.

PM1 The variant p.Met163Lys does not lie within a statistically significant mutational hotspot (cancerhotspots.org negative) and no literature establishes a well-characterized critical functional domain encompassing position 163.

PM5 No pathogenic or likely pathogenic missense variant at the same amino acid residue (p.Met163) with a different alteration has been identified.

PM6 No de novo data are available for this variant.

PP1 No cosegregation data are available.

PP2 HCI prior scores are not available for STAG2 (gene not supported in the HCI database).

PP3 Multiple in silico tools predict no significant impact.

PP4 No patient phenotype or clinical data are available for review.

PP5 NM_001042749.1:c.488T>A is absent from ClinVar.

Benign

BA1 NM_001042749.1:c.488T>A is absent from all population databases (gnomAD v2.1, v4.1, and Canada; allele count = 0).

BS1 NM_001042749.1:c.488T>A is absent from all population databases.

BS2 No data are available regarding observation of this variant in healthy adults.

BS3 No well-established functional studies demonstrate a neutral or benign effect for this variant.

BS4 No segregation data are available for this variant.

BP1 BP1 requires that the gene primarily causes disease through a truncating mechanism and that missense variants are an uncommon cause of disease.

BP2 No data are available on whether this variant has been observed in trans with a known pathogenic variant.

BP5 No data are available regarding an alternative molecular basis for disease in the proband.

BP6 NM_001042749.1:c.488T>A is absent from ClinVar.

N/A · 1 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 = 0.01). BayesDel score = -0.143023.

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. STAG2, a component of the cohesin complex, is recurrently altered by mutation in various cancer types.

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