ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function 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)

Evidence for Triplosenstive Phenotype

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.