ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7456C>T (p.Arg2486Ter) (rs587779865)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212068 SCV000149160 pathogenic not provided 2017-11-06 criteria provided, single submitter clinical testing This variant is denoted ATM c.7456C>T at the cDNA level and p.Arg2486Ter (R2486X) 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. ATM Arg2486Ter has been reported in patients with breast or pancreatic cancer and in the homozygous and compound heterozygous states in individuals with Ataxia-telangiectasia (Buzin 2003, Meneret 2014, Susswein 2016, Takai 2016). We therefore consider this variant to be pathogenic.
Ambry Genetics RCV000115251 SCV000213694 pathogenic Hereditary cancer-predisposing syndrome 2018-06-18 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae RCV000462583 SCV000547106 pathogenic Ataxia-telangiectasia syndrome 2019-10-16 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg2486*) in the ATM gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported as heterozygous in an individual with breast cancer (PMID: 26681312), and as homozygous in an individual with ataxia-telangiectasia (PMID: 12552559). ClinVar contains an entry for this variant (Variation ID: 127445). Loss-of-function variants in ATM are known to be pathogenic (PMID: 25614872, 23807571). For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000212068 SCV000780405 likely pathogenic not provided 2018-02-28 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000462583 SCV001361262 pathogenic Ataxia-telangiectasia syndrome 2019-06-13 criteria provided, single submitter clinical testing Variant summary: ATM c.7456C>T (p.Arg2486X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.2e-05 in 251264 control chromosomes. c.7456C>T has been reported in the literature in multiple individuals affected with Ataxia-Telangiectasia (Buzin_2003, Micol_2011, Meneret_2014). Heterozygous mutations in ATM are a risk allele for malignancies, and this mutation has also been reported in the literature in individuals with breast and other cancers (Takai_2016, Susswein_2016, Sun_2017, Ohmoto_2018, and Yang_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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.