UBE2A

Overview

UBE2A (ubiquitin-conjugating enzyme E2 A) is an E2 ubiquitin-conjugating enzyme involved in DNA damage tolerance and post-replication repair. Germline mutations at codon 7 (p.Arg7Trp) cause X-linked intellectual disability. In cancer genomics, recurrent somatic gain-of-function codon-6 hotspot mutations have been identified as a novel candidate driver in endometrial polyps.

Alterations observed in the corpus

  • Recurrent somatic hotspot mutations at codon 6: p.(Arg6Trp) (4 polyps) and p.(Arg6del) (1 polyp) across 77 endometrial polyps; mean VAF 0.28 in WGS discovery cohort — clonally dominant relative to other low-VAF mutations in the same samples PMID:28445112.
  • UBE2A p.(Arg6Trp) predicted likely pathogenic by AlphaMissense (score 0.96), CADD (24.4), and REVEL (0.56); predicted structurally stabilizing by DynaMut (ΔΔG = +1.650 kcal/mol on PDB 6CYO); authors propose gain-of-function mechanism PMID:28445112.
  • OncodriveCLUST score 0.83 (q = 1.51 × 10⁻⁵) confirms clustering of mutations at codon 6 as statistically non-random PMID:28445112.
  • p.(Arg6Trp) also observed in a TCGA endometrial cancer sample (C3N-00386) and in NSCLC, colorectal, and pancreatic samples in cBioPortal, suggesting broader cancer relevance PMID:28445112.

Cancer types (linked)

  • Endometrial polyps (benign precursor lesions related to UCEC): 5/77 (6.5%) polyps carry codon-6 UBE2A mutations across discovery and validation cohorts PMID:28445112.

Co-occurrence and mutual exclusivity

  • UBE2A codon-6 mutations co-occur with HMGA1/HMGA2 rearrangements in some polyps; the relative timing and clonal hierarchy are not established PMID:28445112.

Therapeutic relevance

  • No targeted therapy proposed; direct functional validation of UBE2A gain-of-function in polyp-relevant models has not been performed PMID:28445112.

Open questions

  • Functional validation of the proposed gain-of-function effect of UBE2A p.(Arg6Trp/del) in polyp biology is lacking PMID:28445112.
  • Relationship to the germline UBE2A p.(Arg7Trp) X-linked intellectual disability allele suggests the region is functionally sensitive, but the cancer-relevant mechanism is distinct from the neurological phenotype PMID:28445112.

Sources

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