ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.748C>T (p.Arg250Ter) (rs772821016)

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
Academic Department of Medical Genetics, University of Cambridge RCV000216766 SCV000992200 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 RCV000216766 SCV000275923 pathogenic Hereditary cancer-predisposing syndrome 2018-03-27 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 RCV000216766 SCV000904432 pathogenic Hereditary cancer-predisposing syndrome 2018-02-16 criteria provided, single submitter clinical testing
Counsyl RCV000196975 SCV000486919 pathogenic Ataxia-telangiectasia syndrome 2016-09-07 criteria provided, single submitter clinical testing
GeneDx RCV000479464 SCV000566881 pathogenic not provided 2018-12-10 criteria provided, single submitter clinical testing This pathogenic variant is denoted ATM c.748C>T at the cDNA level and p.Arg250Ter (R250X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA). In addition, ATM Arg250Ter has also been shown to result in skipping of exon 9 (Teraoka 1999, Nakamura 2012). Both the nonsense and aberrant splicing alterations are predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in at least one individual with breast cancer and in the compound heterozygous state in at least four individuals with ataxia-telangiectasia (Teraoka 1999, Buzin 2002, Broccoletti 2011, Nakamura 2012, Sun 2017). Based on currently available evidence, we consider this variant to be pathogenic.
Invitae RCV000196975 SCV000253745 pathogenic Ataxia-telangiectasia syndrome 2018-11-08 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg250*) in the ATM gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs772821016, ExAC 0.009%). This variant has been observed in compound heterozygous state in several individuals affected with ataxia-telangiectasia (PMID: 10330348, 12552559, 22006793) and as heterozygous in an individual with breast cancer (PMID: 28724667). ClinVar contains an entry for this variant (Variation ID: 216024). Experimental studies have shown that this change results in exon 7 skipping (reported as exon 9 in the literature) (PMID: 22006793, 10330348). Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). For these reasons, this variant has been classified as Pathogenic.
Mendelics RCV000196975 SCV000838476 pathogenic Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing

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.