ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.5623C>T (p.Arg1875Ter) (rs376603775)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Academic Department of Medical Genetics, University of Cambridge RCV000493350 SCV000992201 pathogenic Hereditary cancer-predisposing syndrome 2018-01-26 criteria provided, single submitter research Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity.
Ambry Genetics RCV000493350 SCV000581455 pathogenic Hereditary cancer-predisposing syndrome 2017-09-18 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 RCV000493350 SCV000913964 pathogenic Hereditary cancer-predisposing syndrome 2017-11-07 criteria provided, single submitter clinical testing
GeneDx RCV000236653 SCV000292957 pathogenic not provided 2018-05-07 criteria provided, single submitter clinical testing This pathogenic variant is denoted ATM c.5623C>T at the cDNA level and p.Arg1875Ter (R1875X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in association with breast cancer and, in the homozygous state, Ataxia-telangiectasia (A-T) (Gilad 1998, Teraoka 1999, Goldgar 2011, Keimling 2011). In addition, cell lines from two patients with A-T were used to show that this variant results in no ATM protein expression, defective phosphorylation of downstream target genes, and a damaging effect on double strand break repair function similar to a BRCA1 pathogenic variant (Keimling 2011). This variant is considered pathogenic.
Invitae RCV000540911 SCV000622605 pathogenic Ataxia-telangiectasia syndrome 2018-12-31 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg1875*) in the ATM gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs376603775, ExAC 0.003%). This variant has been observed in an individual affected with breast cancer (PMID: 26976419), and in the homozygous or compound heterozygous state in individuals affected with ataxia-telangiectasia (PMID: 9450906, 10873394, 21792198, 27980538). ClinVar contains an entry for this variant (Variation ID: 245815). Loss-of-function variants in ATM are known to be pathogenic (PMID: 25614872, 23807571). For these reasons, this variant has been classified as Pathogenic.

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