STAG2 c.549dup, p.Arg184ThrfsTer6
NM_001042749.1:c.549dup
Pathogenic
Pathogenic classification based on PVS1 (Very Strong LoF), PS3 (Strong functional evidence), and PM2 (Moderate population absence), with no conflicting benign evidence.
ACMG/AMP Criteria Applied
PVS1
PS3
PM2
Genetic Information
Gene & Transcript Details
Gene
STAG2
Transcript
NM_001042749.2
Total Exons
35
Strand
Forward (+)
Reference Sequence
NC_000023.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_001042749.1 | Alternative | 35 exons | Forward |
Variant Details
HGVS Notation
NM_001042749.1:c.549dup
Protein Change
R184Tfs*6
Location
Exon 8
(Exon 8 of 35)
5'Exon Structure (35 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 184 in gene STAG2
Variant interpretation based on transcript NM_001042749.2
Genome Browser
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HGVS InputNM_001042749:c.549dup
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Unknown
Publications (0)
No publication details.
Clinical Statement
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 184 in gene STAG2
Functional Summary
The STAG2 R184Tfs*6 variant is a truncating mutation in a tumor suppressor gene, leading to likely loss of function. Functional studies indicate that truncating mutations in STAG2 result in loss of protein expression, likely due to nonsense-mediated mRNA decay. Depletion of STAG2 in certain cancer cell lines causes significant chromosomal abnormalities, highlighting its role in maintaining chromosomal stability. Correction of STAG2 mutations in glioblastoma cell lines restores sister chromatid cohesion and reduces chromosomal instability. However, in AML patients, STAG2 truncating mutations do not lead to chromosomal aberrations, and patients maintain a normal karyotype. Overall, the functional evidence supports a damaging effect of the STAG2 R184Tfs*6 variant.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Very Strong)
According to standard ACMG guidelines, the rule for PVS1 is: Null variant in a gene where loss of function (LoF) is a known mechanism of disease (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon deletion in a LoF gene). The evidence for this variant shows that NM_001042749.1:c.549dupA causes a frameshift (R184Tfs*6) resulting in a premature stop codon in STAG2, and LoF is the established disease mechanism. Therefore, this criterion is applied at Very Strong strength because it meets the definition of a null variant in a gene with known LoF mechanism.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: Same amino acid change as a known pathogenic variant but different nucleotide change. The evidence for this variant shows no other variant has been reported causing the same R184 change as pathogenic. Therefore, this criterion is not applied because there is no known pathogenic variant with the same amino acid change.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Parental testing has not been performed for this variant. Therefore, this criterion is not applied because de novo status is unconfirmed.
PS3
PS3 (Strong)
According to standard ACMG guidelines, the rule for PS3 is: Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. The evidence for this variant shows that truncating mutations in STAG2 lead to loss of protein expression likely via nonsense-mediated decay and cause chromosomal instability in cell models, supporting a damaging effect. Therefore, this criterion is applied at Strong strength because functional studies demonstrate a damaging effect.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: Prevalence in affected individuals significantly increased compared with controls. No case-control prevalence data are available for this variant. Therefore, this criterion is not applied due to lack of statistical evidence from case-control studies.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: Located in a mutational hot spot or well-established functional domain without benign variation. There is no evidence that R184Tfs*6 lies within a known hot spot or critical domain beyond general LoF. Therefore, this criterion is not applied.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: Absent from controls (or at extremely low frequency if recessive). The evidence for this variant shows it is absent from gnomAD and other population databases (MAF=0%). Therefore, this criterion is applied at Moderate strength because the variant is not present in population controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: Detected in trans with a pathogenic variant for recessive disorders. There is no information on allelic phase or a second pathogenic variant. Therefore, this criterion is not applied due to lack of trans configuration data.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: Protein length changes due to in-frame deletions/insertions or stop-loss variants. The variant is a frameshift, not an in-frame indel or stop-loss. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: Novel missense change at an amino acid residue where a different pathogenic missense change has been seen. This is a frameshift variant, not a missense change. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: Assumed de novo, but without confirmation of paternity and maternity. There is no de novo evidence provided. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: Co-segregation with disease in multiple affected family members. No family segregation data are available for this variant. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: Missense variant in a gene with low rate of benign missense variation and where missense variants are a common mechanism of disease. This variant is a frameshift, not missense. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP3 is: Multiple lines of computational evidence support a deleterious effect on the gene/gene product. In silico predictions for splicing (SpliceAI score 0.19) are below significance thresholds and computational tools are not informative for a frameshift. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: Patient's phenotype or family history highly specific for a disease with a single genetic etiology. No specific clinical phenotype or family history data are provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: Reputable source reports variant as pathogenic without accessible evidence. There are no such reports. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: Allele frequency is too high for the disorder. The variant is absent in population databases, not above any threshold. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: Allele frequency is greater than expected for the disorder. The variant is absent and does not exceed any expected frequency. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: Observed in healthy individuals with full penetrance expected at an early age. No healthy individual observations are reported. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: Well-established functional studies show no damaging effect on protein function or splicing. Existing functional studies show a damaging effect. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: Lack of segregation in affected family members. No segregation data are available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: Missense variant in a gene where only LoF causes disease. The variant is frameshift. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant. No cis/trans data with other variants are reported. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: In-frame deletions/insertions in a repetitive region without known function. The variant is a frameshift duplication, not an in-frame event. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP4 is: Multiple lines of computational evidence suggest no impact. Computational predictions are not applicable for a clear LoF frameshift. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: Variant found in a case with an alternate molecular basis for disease. No such alternate findings are reported. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: Reputable source reports variant as benign without accessible evidence. There are no benign reports. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: Synonymous variant with no predicted impact on splicing. This is not a synonymous variant. Therefore, this criterion is not applied.