NM_001042749.1:c.482T>A

STAG2 · NP_001036214.1:p.(Leu161His) · NM_001042749.1

GRCh37: chrX:123179033 T>A · GRCh38: chrX:124045183 T>A

Gene: STAG2 Transcript: NM_001042749.1

Final call

VUS

PM2 moderate BP4 supporting benign

Variant details

Gene

STAG2

Transcript

NM_001042749.1

Protein

NP_001036214.1:p.(Leu161His)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_001042749.1:c.482T>A (p.Leu161His) in STAG2 is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at moderate strength, though X-chromosome coverage caveats apply.

SpliceAI predicts no splice impact (max delta 0.01) and BayesDel score is 0.0859 (low/benign range), meeting BP4 at supporting benign strength.

This variant is absent from ClinVar and COSMIC and has not been reported in the literature; no functional, segregation, or case-control data are available for variant-specific assessment.

With 1 moderate pathogenic criterion (PM2) and 1 supporting benign criterion (BP4), this variant does not meet the threshold for Likely Pathogenic or Likely Benign under generic ACMG/AMP 2015 combination rules (PMID:25741868). The variant is classified as a Variant of Uncertain Significance (VUS).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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
BP3	N/A	BP3 applies to in-frame deletions/insertions in non-repetitive regions; this is a missense substitution.
PM3	N/A	PM3 applies to recessive disorders (variant detected in trans with a pathogenic variant); STAG2-related disease is not established as recessive and no phase data available.
PM4	N/A	PM4 applies to protein-length changes from non-frameshift indels or stop-loss variants; this is a missense substitution.
PVS1	Not met	PVS1 is reserved for null variants (nonsense, frameshift, canonical ±1,2 splice sites, initiation codon, or exon-level deletions) under the ClinGen SVI framework (PMC6185798). This is a missense variant (p.Leu161His) and does not fall into any null-variant bucket.	pvs1_generic_framework
PS1	Not met	Requires the same amino acid change (p.Leu161His) to have been previously established as pathogenic. This variant is absent from ClinVar and no literature reports this exact amino acid change as pathogenic.	clinvar
PS2	Not met	Requires a confirmed de novo observation with both maternity and paternity confirmed. No family or trio data are available for this variant.
PS3	Not met	Requires well-established in vitro or in vivo functional studies demonstrating a damaging effect. No variant-specific functional data were identified; OncoKB reports Unknown Oncogenic Effect with no variant-specific reviewed evidence. The five reviewed publications provide only gene-level context and none tested this variant experimentally.	oncokb
PS4	Not met	Requires a statistically higher prevalence of the variant in affected individuals versus controls. This variant is absent from ClinVar and COSMIC; no case-control data are available.	clinvar
PS5	Not met	Requires a reputable source to have recently attributed pathogenicity to this variant. The variant is absent from ClinVar and no literature reports it as pathogenic.	clinvar
PM1	Not met	Requires the variant to lie in a mutational hotspot or a well-characterized critical functional domain without benign variation. The residue L161 is not reported as a statistically significant hotspot by cancerhotspots.org, and no literature was identified that characterizes the region around position 161 as a critical functional domain with intolerance to missense variation.	oncokb
PM2	Met	Absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0, meeting the PM2 threshold of <0.1% allele frequency in large population databases. Note: STAG2 is located on the X chromosome; absence from gnomAD should be interpreted with awareness of potentially reduced X-chromosome coverage in some regions.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	Requires a different pathogenic missense change at the same residue (Leu161). No same-residue pathogenic comparator variants were identified in ClinVar, and the automated PM5 candidate search returned zero candidates.	pm5_candidates clinvar
PM6	Not met	Requires a de novo observation without confirmation of paternity and maternity. No de novo data are available for this variant.
PP1	Not met	Requires cosegregation of the variant with disease in multiple affected family members. No family or segregation data are available.
PP2	Not assessed	Requires evidence that STAG2 has a low rate of benign missense variation and that missense variants are a common mechanism of disease. No gene-level constraint metrics (missense Z-score, gnomAD constraint, pLI) were available in the evidence packet, and HCI prior scores were not available for STAG2.
PP3	Not met	Requires multiple lines of computational evidence to support a deleterious effect on the gene product. SpliceAI predicts no splice impact (max delta 0.01), and BayesDel score is 0.086 (low, consistent with a benign prediction). REVEL is unavailable. The available computational evidence does not support a deleterious effect.	spliceai bayesdel
PP4	Not assessed	Requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology. No clinical phenotype or family history was provided for assessment.
PP5	Not met	Requires a reputable source (e.g., ClinVar expert panel, clinical diagnostic laboratory) to have recently reported the variant as pathogenic. The variant is absent from ClinVar with no submissions of any kind.	clinvar
BA1	Not met	Requires an allele frequency >1% in population databases (non-VCEP rule). The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. It does not meet the BA1 frequency threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Requires an allele frequency >0.3% in population databases (non-VCEP rule). The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. It does not meet the BS1 frequency threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Requires observation of the variant in a healthy adult individual for a disorder with full penetrance expected at an early age. No individual-level phenotype data are available for any carriers, and no carriers were identified in population databases.
BS3	Not met	Requires well-established in vitro or in vivo functional studies showing no damaging effect on protein function or splicing. No functional studies have been performed on this variant. BayesDel score (0.086) is a computational prediction and does not qualify as well-established functional evidence.	bayesdel spliceai
BS4	Not met	Requires lack of segregation with disease in affected family members. No family or segregation data are available for this variant.
BP1	Not met	Requires the variant to be a missense change in a gene for which primarily truncating variants cause disease. While some STAG2 disease-associated variants are truncating (PMID:41492387 describes STAG2-truncating variants in germline disease), the literature also describes pathogenic missense STAG2 variants in both somatic and germline contexts. There is insufficient evidence that only truncating variants cause STAG2-related disease.
BP2	Not assessed	Requires observation of the variant in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a known pathogenic variant. No phase data are available.
BP4	Met	Multiple lines of computational evidence suggest no impact on the gene product or splicing. SpliceAI predicts no significant splice impact (max delta score 0.01), and BayesDel score is 0.086 (low, consistent with a benign effect on protein function). Two independent in silico tools support a neutral or benign interpretation.	spliceai bayesdel
BP5	Not met	Requires the variant to be found in a case with an alternate molecular basis for disease. No such data are available.
BP6	Not met	Requires a reputable source to have recently reported the variant as benign. The variant is absent from ClinVar with no submissions of any kind.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact; this is a missense variant (p.Leu161His) and does not qualify.

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.