ClinVar Miner

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

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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).
Ambry Genetics RCV000573086 SCV000667936 pathogenic Hereditary cancer-predisposing syndrome 2016-06-02 criteria provided, single submitter clinical testing 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
Invitae RCV001203956 SCV001375141 pathogenic Ataxia-telangiectasia syndrome 2019-07-29 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp2483*) in the ATM gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs773516672, ExAC 0.02%). This variant has been observed in individuals affected with ataxia-telangiectasia. It is a common disease-causing allele in the Costa Rican population (PMID: 9443866, 9682216). ClinVar contains an entry for this variant (Variation ID: 245972). Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). For these reasons, this variant has been classified as Pathogenic.

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