ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

  • 11q22.3
  • GRCh37/hg19 chr11: 108,093,559-108,239,826
  • View: NCBI | Ensembl | UCSC
  • GRCh38/hg38 chr11: 108,222,484-108,369,102
  • View: NCBI | Ensembl | UCSC
Select assembly: (NC_000011.9) (NC_000011.10)
Evidence for haploinsufficiency phenotype
PubMed ID Description
3574400 This study examined the cancer incidence of individuals with heterozygous pathogenic variants in over 120 families with ataxia telangiectasia (A-T). The cancer incidence in adult blood relatives of A-T individuals were compared to their adult spouses. The adjusted cancer rate ratio was 1.6 for males (P=0.032) and 2 for females (P=0.013) and a relative risk of 2.3 (p=0.014) for males and 3.1 (P=0.004). Breast cancer was the most common site with a relative risk of 6.8 (P=0.006).
27595995 The study examined the association of PALB2, CHEK2, and ATM with breast cancer. The p.Val2424Gly variant in the ATM gene was found to be associated with breast cancer with an OR of 11.6 (1.50 to 89.9) (p= 0.0012). This variant has been observed either as homozygous or compound heterozygous with another pathogenic variant in the gene in individuals with A-T (PMID: 9463314, 8755918). Furthermore, experimental studies have demonstrated that the variant leads to loss of kinase activity and therefore loss of function (PMID: 11382771, 11830610, 18634022, 19431188)
15928302 In a cohort of 1160 relatives in 132 families with at least one patient with A-T, and either a loss of function, in-frame, or a missense variant. Statistically significant association with female breast cancer was found among the heterozygous carriers (RR = 2.23, 95% CI = 1.16 to 4.28) when compared to the control cohort. The cumulative cancer risk among heterozygous of A-T carriers is 8.8% (95% CI = 3.5% to 21.4%) by age 50 years and 16.6% (95% CI = 9.1% to 29.3%) by age 80 years. There was no statistically significant difference in the cancer risks among individuals with different variant types.

Haploinsufficiency phenotype comments:

PMIDS: 11830610, 15928302, 16832357, 16958054, 21787400, 27595995, 22585167, 26098866, 26483394, 27433846, 27324988, 27989354

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