ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.790del (p.Tyr264fs) (rs587781978)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130373 SCV000185227 pathogenic Hereditary cancer-predisposing syndrome 2018-08-23 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae RCV000233840 SCV000283066 pathogenic Ataxia-telangiectasia syndrome 2019-12-27 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr264Ilefs*12) in the ATM gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs774609577, ExAC 0.001%). This variant has been observed in individuals affected with ataxia-telangiectasia (PMID: 9887333, 12673797, 12815592, 22213089, 15928302), and with breast or ovarian cancer (PMID: 16832357, 24549055). ClinVar contains an entry for this variant (Variation ID: 141742). Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000235917 SCV000293219 pathogenic not provided 2018-07-30 criteria provided, single submitter clinical testing This deletion of one nucleotide in ATM is denoted c.790delT at the cDNA level and p.Tyr264IlefsX12 (Y264IfsX12) at the protein level. The normal sequence, with the base that is deleted in brackets, is GCTT[delT]ATAT. The deletion causes a frameshift, which changes a Tyrosine to an Isoleucine at codon 264, and creates a premature stop codon at position 12 of the new reading frame. It is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This pathogenic variant has been reported in several individuals with a clinical diagnosis of Ataxia-telangiectasia (A-T) and in individuals with personal and/or family history of breast, ovarian, or prostate cancer (Sandoval 1999, Li 2000, Mitui 2003, Buzin 2003, Thompson 2005, Renwick 2006, Castera 2014, Pritchard 2016, Decker 2017, Kraus 2017). Furthermore, Verhagen et al. (2012) studied this variant in a patient with A-T who also carried another truncating variant and reported absence of the ATM protein in this individual. We consider this variant to be pathogenic.
Color RCV000130373 SCV000687801 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000233840 SCV000694362 pathogenic Ataxia-telangiectasia syndrome 2017-05-02 criteria provided, single submitter clinical testing Variant summary: The ATM c.790delT (p.Tyr264Ilefs) variant results in a premature termination codon, predicted to cause a truncated or absent ATM 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 (e.g., c.1027_1030delGAAA [p.Glu343fs). One in silico tool predicts a damaging outcome for this variant. The variant has been identified in numerous patients affected with ataxia telangiectasia and/or breast cancer and has not been observed in healthy individuals (e.g., Renwick_2006; Buzin_2003; Castera_2014). In addition, a functional study revealed that a patient carrying the variant of interest and a second truncating ATM variant (c.1563_1564delAG [p.Glu522fs]) had no detectable ATM expression or kinase activity (Verhagen_HM_2012), suggesting the variant is a functional null allele. This variant is absent in the large control database ExAC (0/122508 control chromosomes). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000235917 SCV001334468 pathogenic not provided 2020-04-01 criteria provided, single submitter clinical testing
Division of Human Genetics,Children's Hospital of Philadelphia RCV000233840 SCV000536866 pathogenic Ataxia-telangiectasia syndrome 2016-05-05 no assertion criteria provided research

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.