TOP2A

Chr 17

DNA topoisomerase II alpha

Also known as: TOP2, TOP2alpha, TOPIIA, TP2A

This gene encodes a DNA topoisomerase, an enzyme that controls and alters the topologic states of DNA during transcription. This nuclear enzyme is involved in processes such as chromosome condensation, chromatid separation, and the relief of torsional stress that occurs during DNA transcription and replication. It catalyzes the transient breaking and rejoining of two strands of duplex DNA which allows the strands to pass through one another, thus altering the topology of DNA. Two forms of this enzyme exist as likely products of a gene duplication event. The gene encoding this form, alpha, is localized to chromosome 17 and the beta gene is localized to chromosome 3. The gene encoding this enzyme functions as the target for several anticancer agents and a variety of mutations in this gene have been associated with the development of drug resistance. Reduced activity of this enzyme may also play a role in ataxia-telangiectasia. [provided by RefSeq, Jul 2010]

Primary Disease Associations & Inheritance

DNA topoisomerase II, resistance to inhibition of, by amsacrine
2
Active trials
141
ClinVar variants
8
Pathogenic / LP
4.0
Missense Z· constrained
0.29
LOEUF· LoF intolerant
15
Pubs (2 yr)
Clinical SummaryTOP2A
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.
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ClinVar Variants
8 Pathogenic / Likely Pathogenic· 103 VUS of 141 total submissions
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Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available
Some data sources returned errors (1)

ensembl: Error: Ensembl fetch failed: 500 for https://rest.ensembl.org/lookup/symbol/homo_sapiens/TOP2A?content-type=application/json&expand=1

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Dual constrained — LoF & missense intolerant
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.29LOEUF
pLI 0.991
Z-score 6.75
OE 0.19 (0.120.29)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
4.04Z-score
OE missense 0.59 (0.540.64)
448 obs / 762.0 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.19 (0.120.29)
00.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.59 (0.540.64)
00.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.86
01.21.6
LoF obs/exp: 15 / 80.2Missense obs/exp: 448 / 762.0Syn Z: 1.70

ClinVar Variant Classifications

141 submitted variants in ClinVar

Classification Summary

Pathogenic8
VUS103
Likely Benign20
Benign9
Conflicting1
8
Pathogenic
103
VUS
20
Likely Benign
9
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
8
0
8
Likely Pathogenic
0
0
0
0
0
VUS
0
102
1
0
103
Likely Benign
0
12
1
7
20
Benign
0
2
1
6
9
Conflicting
1
Total01161113141

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

TOP2A · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

DNA topoisomerase II, resistance to inhibition of, by amsacrine

Molecular basis of disorder known

Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Predicting Anthracycline Benefit: TOP2A and CEP17-Not Only but Also.
Bartlett JM et al.·J Clin Oncol
2015Meta-analysis
Top 10 resultsSearch PubMed ↗