ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8977C>T (p.Arg2993Ter) (rs770641163)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165909 SCV000216664 pathogenic Hereditary cancer-predisposing syndrome 2018-04-13 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),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Structural Evidence
Color RCV000165909 SCV000687865 pathogenic Hereditary cancer-predisposing syndrome 2017-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000169469 SCV000220908 likely pathogenic Ataxia-telangiectasia syndrome 2014-11-24 criteria provided, single submitter literature only
Dr. Peter K. Rogan Lab,Western University RCV000416708 SCV000262587 likely pathogenic Hereditary breast and ovarian cancer syndrome 2015-12-22 no assertion criteria provided research Sequenced patient with familial breast cancer
Fulgent Genetics,Fulgent Genetics RCV000515430 SCV000611169 pathogenic Familial cancer of breast; Ataxia-telangiectasia syndrome 2017-05-18 criteria provided, single submitter clinical testing
GeneDx RCV000414034 SCV000490415 pathogenic not provided 2018-11-24 criteria provided, single submitter clinical testing This variant is denoted ATM c.8977C>T at the cDNA level and p.Arg2993Ter (R2993X) 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 lead to protein truncation. This variant has been reported in both the homozygous and compound heterozygous state in multiple patients with ataxia telangiectasia (Li 2000, Sun 2002, Mitui 2003, Claret Teruel 2005, Magliozzi 2006, Chessa 2009, Carranza 2017), and in at least one individual with breast cancer (Caminsky 2016). The disrupted region at the end of the gene is located the FATC domain (Stracker 2013). We consider ATM Arg2993Ter to be pathogenic.
GeneKor MSA RCV000165909 SCV000821704 pathogenic Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000169469 SCV000694387 pathogenic Ataxia-telangiectasia syndrome 2016-10-14 criteria provided, single submitter clinical testing Variant summary: The ATM c.8977C>T (p.Arg2993X) 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. One in silico tool predicts a damaging outcome for this variant. This variant was found in 2/121398 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). The variant has been reported in publications in affected individuals both in the homozygous and compound heterozygous state. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000169469 SCV000283099 pathogenic Ataxia-telangiectasia syndrome 2018-12-20 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal at codon 2993 (p.Arg2993*) located within the last 15 codons of the penultimate exon in the ATM mRNA. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated ATM protein. This variant is present in population databases (rs770641163, ExAC 0.003%). This variant has been reported as homozygous and in trans with second pathogenic ATM variants in several individuals affected with ataxia-telangiectasia (A-T) (PMID: 12815592, 23322442, 17124347, 16238588, 20840352). It has also been reported in an individual with chronic lymphocytic leukemia (PMID: 21933854). ClinVar contains an entry for this variant (Variation ID: 186330). An experimental study showed loss of kinase activity in cells derived from a homozygous A-T patient carrying this variant (PMID: 23774824). For these reasons, this variant has been classified as Pathogenic.

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