ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.7913G>A (p.Trp2638Ter) (rs377349459)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129649 SCV000184447 pathogenic Hereditary cancer-predisposing syndrome 2018-06-01 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000212077 SCV000209648 pathogenic not provided 2018-06-22 criteria provided, single submitter clinical testing This pathogenic variant is denoted ATM c.7913G>A at the cDNA level and p.Trp2638Ter (W2638X) at the protein level. The substitution creates a nonsense variant, which changes a Tryptophan to a premature stop codon (TGG>TAG), 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 classical ataxia-telangiectasia patients in both the homozygous and compound heterozygous states (Sasaki 1998, Mitui 2003, Coutinho 2004, Demuth 2011), and has also been reported in the heterozygous state in at least one individual with prostate cancer (Pritchard 2016). We consider this variant to be pathogenic.
Counsyl RCV000169621 SCV000221148 likely pathogenic Ataxia-telangiectasia syndrome 2015-02-19 criteria provided, single submitter literature only
Invitae RCV000169621 SCV000253746 pathogenic Ataxia-telangiectasia syndrome 2019-12-26 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp2638*) in the ATM gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs377349459, ExAC 0.01%). This variant has been reported in the homozygous or compound heterozygous state in individuals and families affected with ataxia-telangiectasia (PMID: 9711876, 12815592, 15039971, 21965147). It was also observed in an individual with colon cancer and an individual with prostate cancer (PMID: 26681312, 27433846). ClinVar contains an entry for this variant (Variation ID: 141233). Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). For these reasons, this variant has been classified as Pathogenic.
Color RCV000129649 SCV000687802 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000169621 SCV000694363 pathogenic Ataxia-telangiectasia syndrome 2017-05-15 criteria provided, single submitter clinical testing Variant summary: The ATM c.7913G>A (p.Trp2638X) 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.8264_8268delATAAG, p.Tyr2755fsX12; c.8266A>T, p.Lys2756X; c.8287C>T, p.Arg2763X; c.8977C>T, p.Arg2993X). The variant of interest has been found in ExAC in 1/120514 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0039528). This variant was reported in several patients with Ataxia Telangiectasia (A-T) in homozygous state as well as in compound heterozygous state with other pathogenic/ likely pathogenic variants (Sasaki_Hum Mutat_1998, Coutinho_AmJMedGenet_2004, Demuth_Neurogenetics_2011, Nakamura_Mol Genet Genomic Med_2014). Protein expression and ATM-dependent kinase activity assays from patient cells carrying this variant in heterozygous state and compound heterozygous state with another truncating variant are consistent with the predicted outcome (Fernet_BrJC_2004, Nakamura_Mol Genet Genomic Med_2014). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic.
Mendelics RCV000169621 SCV000838603 pathogenic Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000768151 SCV000898530 pathogenic Familial cancer of breast; Ataxia-telangiectasia syndrome 2018-01-18 criteria provided, single submitter clinical testing ATM NM_000051.3 exon 53 p.Trp2638* (c.7913G>A): This variant has been identified as homozygous or compound heterozygous in at least 6 individuals with ataxia telangiectasia (Sasaki 1998 PMID:9711876, Mitui 2003 PMID:12815592, Coutinho 2004 PMID:15039971, Demuth 2011 PMID:21965147). This variant was also identified in at least 2 individuals with colon or prostate cancer (Pritchard 2016 PMID:27433846, Susswein 2016 PMID:26681312). This variant is present in 4/24010 African alleles in the Genome Aggregation Database ( Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic or likely pathogenic (Variation ID:141233). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant creates a premature stop at this codon which results in an absent or abnormal protein. Loss of function variants are a known mechanism of disease for this gene (Huang 2013 PMID:23807571) . In summary, this variant is classified as pathogenic.

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