ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000008.10) (NC_000008.11)
  • Haploinsufficiency score: 3
  • Strength of Evidence (disclaimer): Sufficient evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
17957789 Bogdanova N, et al. the 657del5 variant was identified in 15/1,588 breast cancer cases (0.9%) from Belarus and in 1/1,076 cases (0.1%) from Germany but in only 1/1,014 population controls from Belarus and 0/1017 German controls (p < 0.01). Also reviewed four other publications and combined with their results: 56/6812 (0.8%) breast cancer patients with 657del5 vs 32/9209 (0.3%) population controls ? OR (95% CI) of 2.8 (1.8; 4.4), p = 1.1 ? 10?5 arrangements.
30590007 Rusak B, et al., 657del5 mutation was detected in 74/5189 unselected breast cancer cases (1.4%) compared to 35/6152 controls (0.6%) , OR, 2.5; p < 0.001; 657del5 present in 15/635 familial cases (2.4%) (OR, 4.2; p < 0.001)
22864661 Zuhlke KA, et al. Identification of a novel NBN truncating mutation in a family with hereditary prostate cancer, novel S706X mutation which results in a truncated NBN protein that lacks the extreme C-terminal ATM recruitment motif, not observed among 2768 unrelated European men (1859 with prostate cancer vs 909 controls)

Haploinsufficiency phenotype comments:

Mutations in NBN are associated with Nijmegen breakage syndrome, an autosomal recessive chromosomal instability syndrome characterized by microcephaly, growth retardation, immunodeficiency, and cancer predisposition. Over 90% of all NBS patients are homozygous for a 5 bp truncating mutation, 657del5. Heterozygous carriers are at an increased for breast cancer, prostate cancer, and possibly other cancers. Importantly most studies are specific to 657del5 variant in Caucasian populations. Per NCCN Guidelines for Genetic/Familial High Risk Assessment: Breast, Ovarian, and Pancreatic, Version 1.2020, ?Current data suggest that breast cancer risks are not increased for pathogenic/likely pathogenic variants other than 657del5? although other truncating variants have been reported. Of note, there are also several additional putative loss of function variants reported as either likely pathogenic or pathogenic by clinical laboratory in ClinVar. These variants have not been described in the literature, and no information is available about the probands in whom they were observed. Other significant literature: PMID: 23765759, PMID: 21514219, PMID: 14973119, PMID: 16770759

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

Triplosensitivity phenotype comment:

No evidence for triplosensitivity