BRCC3

Chr X

BRCA1/BRCA2-containing complex subunit 3

Also known as: BRCC36, C6.1A, CXorf53

NCBI Gene: 79184ENSG00000185515UniProt: P46736

This gene encodes a subunit of the BRCA1-BRCA2-containing complex (BRCC), which is an E3 ubiquitin ligase. This complex plays a role in the DNA damage response, where it is responsible for the stable accumulation of BRCA1 at DNA break sites. The component encoded by this gene can specifically cleave Lys 63-linked polyubiquitin chains, and it regulates the abundance of these polyubiquitin chains in chromatin. The loss of this gene results in abnormal angiogenesis and is associated with syndromic moyamoya, a cerebrovascular angiopathy. Alternative splicing results in multiple transcript variants. A related pseudogene has been identified on chromosome 5. [provided by RefSeq, Jun 2011]

179
ClinVar variants
148
Pathogenic / LP
0.01
pLI score
0
Active trials
Clinical Summary— BRCC3
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.01) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
148 Pathogenic / Likely Pathogenic· 28 VUS of 179 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
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.
0.81LOEUF
pLI 0.006
Z-score 2.08
OE 0.41 (0.23–0.81)
Tolerant

Typical tolerance to LoF variation

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.
2.67Z-score
OE missense 0.29 (0.22–0.39)
32 obs / 111.3 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

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.0.41 (0.23–0.81)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.29 (0.22–0.39)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.88
0≤1.21.6
LoF obs/exp: 6 / 14.6Missense obs/exp: 32 / 111.3Syn Z: 0.62

ClinVar Variant Classifications

179 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic139
Likely Pathogenic9
VUS28
Likely Benign2
Benign1
139
Pathogenic
9
Likely Pathogenic
28
VUS
2
Likely Benign
1
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories· variant type breakdown unavailable

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
————139
Likely Pathogenic
————9
VUS
————28
Likely Benign
————2
Benign
————1
Total—179

Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

BRCC3 · 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

OMIM
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Snail-regulated exosomal microRNA-21 suppresses NLRP3 inflammasome activity to enhance cisplatin resistance.
Cheng HY et al.·J Immunother Cancer
2022
Excessive deubiquitination of NLRP3-R779C variant contributes to very-early-onset inflammatory bowel disease development.
Zhou L et al.·J Allergy Clin Immunol
2021Clinical trial
A bacterial RING ubiquitin ligase triggering stepwise degradation of BRISC via TOLLIP-mediated selective autophagy manipulates host inflammatory response.
Pan X et al.·Autophagy
2025
Pharmacological targeting of NLRP3 deubiquitination for treatment of NLRP3-associated inflammatory diseases.
Ren GM et al.·Sci Immunol
2021
The deubiquitinase BRCC3 increases the stability of ZEB1 and promotes the proliferation and metastasis of triple-negative breast cancer cells.
Huang Q et al.·Acta Biochim Biophys Sin (Shanghai)
2024
BRCC3 mediates inflammation and pyroptosis in cerebral ischemia/reperfusion injury by activating the NLRP6 inflammasome.
Huang X et al.·CNS Neurosci Ther
2024
BRCC3 -Associated Syndromic Moyamoya Angiopathy Diagnosed Through Clinical RNA Sequencing.
Venema M et al.·Clin Genet
2025Case report
High expression of PPP1CC promotes NHEJ-mediated DNA repair leading to radioresistance and poor prognosis in nasopharyngeal carcinoma.
Feng P et al.·Cell Death Differ
2024
Mutations of myelodysplastic syndromes (MDS): An update.
Ganguly BB et al.·Mutat Res Rev Mutat Res
2016Review
BRCC3 mutations in myeloid neoplasms.
Huang D et al.·Haematologica
2015
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools