ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

  • 12q24.33
  • GRCh37/hg19 chr12: 133,200,348-133,264,110
  • View: NCBI | Ensembl | UCSC
  • GRCh38/hg38 chr12: 132,623,758-132,687,519
  • View: NCBI | Ensembl | UCSC
Select assembly: (NC_000012.11) (NC_000012.12)
  • Haploinsufficiency score: 1
  • Strength of Evidence (disclaimer): Little evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
23585368 Smith et al. 2013: A germline intragenic deletion (c.5621 5622delGT) in POLE was found in a patient with advanced colorectal cancer at age 26y, inheritance and family history unknown.
29020732 Eoh et al. 2017: a next-generation sequencing panel of 35 genes run on 117 patients with ovarian cancer identified one patient with a frameshift mutation in POLE.

Haploinsufficiency phenotype comments:

Several studies (see PMID 23263490 Palles et al 2013; PMID 23585368 Smith et al 2013; PMID 24788313 Rohlin et al 2015; PMID 25559809 Chubb et al 2015; PMID 25110875, Kang et al 2015; PMID 25529843 Spier et al 2015; PMID 25860647 Hansen 2016; PMID: 26493165 Rohlin 2016; PMID 27573199 Wimmer 2016 ) report association of missense mutations in POLE (mainly in the exonuclease domain) and early-onset colon cancer and/or colon polyposis. There is emerging evidence that some exonuclease domain missense mutations cause a drastic decrease in fidelity of exonuclease activity for POLE. However, single gene deletions of POLE, or deletions of exons and truncating mutations occurring outside the exonuclease domain, are not as commonly reported. Functional evidence of the impact of these mutations (other than missense exonuclease domain mutations) is sparse.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

No evidence for triplosensitivity.