ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7449G>A (p.Trp2483Ter) (rs773516672)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000573086 SCV000667936 pathogenic Hereditary cancer-predisposing syndrome 2016-06-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Color RCV000573086 SCV000682416 pathogenic Hereditary cancer-predisposing syndrome 2017-03-31 criteria provided, single submitter clinical testing
GeneDx RCV000236176 SCV000293214 pathogenic not provided 2015-10-07 criteria provided, single submitter clinical testing This pathogenic variant is denoted ATM c.7449G>A at the cDNA level and p.Trp2483Ter (W2483X) at the protein level. The substitution creates a nonsense variant, which changes a Tryptophan to a premature stop codon (TGG>TGA) ; however, Eng et al. (2004) have also demonstrated that this variant creates a cryptic splice donor site resulting in a deletion of the last 70 nucleotides of exon 50, previously referred to as exon 52. Consistent with these results, multiple splicing models predict that this variant leads to the creation of a strong cryptic splice donor site. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. ATM c.7449G>A has been reported in multiple patients with Ataxia-telangiectasia and is suggested to be a founder mutation in the Costa Rican population (Telatar 1998, Eng 2004). We consider it to be pathogenic.The ATM protein is a member of the phosphatidylinositol 3-kinase family of proteins that respond to DNA damage by phosphorylating key substrates involved in DNA repair and/or cell cycle control (MIM:607585). Homozygous or compound heterozygous pathogenic variants in the ATM gene are associated with Ataxia-telangiectasia (A-T), an autosomal recessive multisystem disorder characterized by progressive neurodegeneration, telangiectasias, immunodeficiency and increased risk of cancers, particularly for leukemia and lymphoma (MIM:208900, Gatti 2010). Individuals with A-T are also unusually sensitive to ionizing radiation (Gatti 2010). Although symptom onset for A-T typically occurs in childhood, milder adult-onset variant forms of A-T have been reported in individuals with identified homozygous or compound heterozygous pathogenic variants in ATM (McConville 1996, Verhagen 2009, Saunders-Pullman 2012).

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.