ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000003.11) (NC_000003.12)
Evidence for haploinsufficiency phenotype
PubMed ID Description
30159786 de Souza Timoteo AR et al (2018) detected a nonsense variant in ATR (c.3043C>T) in the exon 14 using NGS (targeted capture sequencing) in an individual with bilateral breast cancer (age of diagnosis: 46 and 52 years old) and bone metastasis. Her daughter was negative for this variant by Sanger sequencing. No other family history.
26556299 Schrader KA et al (2016) reported a germline partial deletion of ATR in a breast cancer patient, and a frame-shift variant (c.4915_4918dupGATA, p.T1640fs*21) in a patient with bladder/urinary tract cancer. No family information.
29439820 Antonarakis ES et al (2018) reported a germline splicing variant (c.2634-1G>A) in ATR in a patient with metatatic castration-resistant prostate cancer patient using whole exome sequencing. No family information. 0.2?

Haploinsufficiency phenotype comments:

ATR is one of the main regulators of the DNA damage response. Biallelic loss-of-function variants of ATR are associated with Seckel syndrome (OMIM 210600), a rare autosomal recessive disorder characterized by intrauterine growth retardation, dwarfism, microcephaly with mental retardation, and a characteristic ?bird-headed? facial appearance. Germline heterozygous mutations in ATR have been reported in individuals with variety of cancers, and an increased risk for cancer has been proposed for carriers. Other germline heterozygous deleterious variants (nonsense, frameshift, splicing and partial deletion) have also been reported in different patients with a variety of cancers (breast cancer, ovarian cancer, prostate cancer, gastric cancer, etc). They are c.5342T>A p.L1781* in a breast cancer (26822949), c.3889delG p.V1297fs in breast cancer (30262796), c.4957C>T p.Arg1653X in prostate cancer (27084275), 3 frameshift variants in ovarian cancer (28541631), and c.6075A?T p.Tyr2025X in gastric cancer (29706558). Tanaka A et al (2012) (PMID: 22341969) reported a heterozygous missense variant (c.6431A>G; p.Gln2144Arg) in a large 4-generation family with 24 affected individuals. All had telangiectases that appeared during infancy (before 18 months of age), thinning of the lateral eyebrows and patchy alopecia in areas of skin with prominent telangiectases. In addition, 10 of the 24 cases developed oropharyngeal cancer, typically in the third decade of life or later. Other reported malignancies included nonmelanoma skin cancer (basal cell carcinoma, squamous cell carcinoma, and sebaceous carcinoma) in 3 individuals, breast cancer in 1, and cervical cancer in 1. The variant segregated with the disease and was not found in 220 ethnically matched control chromosomes. The mutation occurs within the important FAT (FRAP, ATM, and TRRAP) domain (which can activate p53) of ATR. The mutation did not lead to a reduction in ATR expression, but cultured fibroblasts showed lower p53 levels after activation of ATR with hydroxyurea than did normal control fibroblasts.

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

Triplosensitivity phenotype comment:

no evidence for triplosensitivity