ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000007.13) (NC_000007.14)
Evidence for haploinsufficiency phenotype
PubMed ID Description
18602922 Authors discuss results of 99 probands who had a Lynch syndrome associated tumor and absence of PMS2 protein by IHC. Total of 55 patients found to have deleterious mutations in PMS2. Most notable was an insertion/deletion mutation in exon 7. Several patients (10 patients) in this study showed deletions of one or more exons , two patients (Patient 28, 29) showed complete gene deletions.
23837913 Authors described the use of long range PCR and MLPA analysis in the identification of deletions within the PMS2 gene. Six patients with suspected Lynch syndrome were identified to have mutations (5 with deletions of one or more exons with loss of PMS2 protein expression by IHC and 1 frameshift mutation). In addition 4 novel VOUS were also identified in this study.
22585707 1) a large (?125 kb) deletion containing the entire PMS2 gene, three other genes (ANKRD61, AIMP2 [JTV1], and EIF2AK1), and a portion of the coding region of RSPH10B. 2) a genomic deletion involving PMS2 exon 8. Special note from this article: Because of the high prevalence of nondeleterious hybrid PMS2 and PMS2CL alleles, the distribution of PMS2 and PMS2CL-specific sequences downstream of exon 12 displays high interindividual variability (Hayward et al., 2007;Ganster et al., 2010; van der Klift et al., 2010). Randomly chosen reference samples of DNA are thus likely to differ widely in terms of the distribution of gene- and pseudogene-derived sequences in this region. This is reflected by high standard deviations for the reference DNA signals generated with all the paralog-discriminating probes located downstream of exon 12 (Supporting Information Fig. S1). It is important to note that an unequal distribution of gene-derived and pseudogene-derived sequences in the reference DNA set will reduce the accuracy of copy number assessments at these loci in patient DNA samples. For this reason, reference DNAs must harbor two PMS2-specific copies and two PMS2CL-specific copies of each sequence bound by paralog-discriminating probes for exons 11-15.

Haploinsufficiency phenotype comments:

Additional PMID: 23837913 (Table2) Multiple novel exonic deletions, nonsense mutations, and frameshift mutations and a splicing mutation (IHC profile: PMS2 absent)

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