ClinVar Miner

Submissions for variant NM_001351834.2(ATM):c.381del (p.Thr127_Val128insTer) (rs587781831)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130118 SCV000184949 pathogenic Hereditary cancer-predisposing syndrome 2018-05-23 criteria provided, single submitter clinical testing The c.381delA pathogenic mutation (also known as p.V128*), located in coding exon 4 of the ATM gene, results from a deletion of one nucleotide at nucleotide position 381. This changes the amino acid from a valine to a stop codon within coding exon 4. This mutation has been reported in multiple ataxia-telangiectasia (A-T) families to date (Babaei M et al. Hum. Genet. 2005 Jul;117(2-3):101-6​; Mitui M et al. Ann. Hum. Genet. 2005 Nov;69(Pt 6):657-64; Podralska MJ et al. Mol. Genet. Genomic Med. 2014 Nov;2(6):504-11). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
GeneDx RCV000478446 SCV000566915 pathogenic not provided 2020-05-26 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in the homozygous and compound heterozygous state in individuals with ataxia telangiectasia (Neubauer 2002, Babaei 2005, Broccoletti 2011); Observed in the heterozygous state in individuals with ATM-related cancers referred for genetic testing at GeneDx and in published literature (Siraj 2017); Not observed at a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 10330348, 26662178, 16266405, 25502423, 15390180, 20840352, 15843990, 11839094, 14970866, 28975465, 28779002, 31850668, 21665257, 22763152, 10425038)
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000478446 SCV000602573 pathogenic not provided 2017-06-13 criteria provided, single submitter clinical testing The c.381delA variant has been previously reported in association with ataxia telangiectasia in multiple unrelated families (Mitui 2005, and Babaei 2005). The c.381delA variant creates a frameshift in the ATM protein at codon 128 in exon 5 which results in a premature termination codon and is predicted to result in a truncated or absent protein product. It is absent from general population databases such as 1000 Genomes, NHLBI GO Exome Sequencing Project (ESP) , and the Exome Aggregation Consortium (ExAC) browser but has been reported to ClinVar (Variation ID: 141546). Based on these observations, the c.381delA variant has been classified as pathogenic.
Color Health, Inc RCV000130118 SCV000687504 pathogenic Hereditary cancer-predisposing syndrome 2020-11-23 criteria provided, single submitter clinical testing This variant deletes 1 nucleotide in exon 5 of the ATM gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with ataxia telangiectasia in compound heterozygous and homozygous state (PMID: 10330348, 10425038, 11839094, 15843990, 20840352). This variant has been identified in 1/251238 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Invitae RCV000627887 SCV000748771 pathogenic Ataxia-telangiectasia syndrome 2020-10-27 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Val128*) 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 to co-occur with different pathogenic ATM variants in individuals affected with ataxia-telangiectasia (A-T) (PMID: 16266405, 15843990, 25502423, 25614872 ). This variant is also known as c.380delA and c.381_381delA in the literature. ClinVar contains an entry for this variant (Variation ID: 141546). Experimental studies in heterozygous cell lines have suggested that this sequence change leads to reduced ATM protein following exposure to radiation (PMID: 14970866). Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000627887 SCV000791538 pathogenic Ataxia-telangiectasia syndrome 2017-05-18 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000627887 SCV000915496 pathogenic Ataxia-telangiectasia syndrome 2018-08-14 criteria provided, single submitter clinical testing The ATM c.381delA (p.Val128Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. Across a selection of the available literature, the p.Val128Ter variant has been found in at least six individuals with ataxia-telangiectasia, all in a compound heterozygous state (Babaei et al. 2005; Mitui et al. 2005; Quarantelli et al. 2013; Podralska et al. 2014). Control data are not available for this variant, which is reported at a frequency of 0.000009 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the collective evidence and the potential impact of frameshift variants, the p.Val128Ter variant is classified as pathogenic for ataxia-telangiectasia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Blueprint Genetics RCV000478446 SCV000927283 likely pathogenic not provided 2017-06-06 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000627887 SCV001360415 pathogenic Ataxia-telangiectasia syndrome 2019-04-01 criteria provided, single submitter clinical testing Variant summary: ATM c.381delA (p.Val128X) 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. The variant allele was found at a frequency of 4.1e-06 in 246028 control chromosomes (gnomAD). c.381delA has been reported in the literature in individuals affected with Ataxia-Telangiectasia (Broccoletti_2011, Micol_2011, Mitui_2005). These data indicate that the variant is likely to be associated with disease. Experimental evidence evaluating an impact on protein function, demonstrated the variant to result in an overall reduced ATM protein level, mRNA level and cell survival after exposure to ionizing radiation (Fernet_2004). Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV001258116 SCV001434989 pathogenic Ataxia-telangiectasia syndrome; Breast cancer, susceptibility to 2019-02-01 criteria provided, single submitter clinical testing The c.381delA (p.Val128*) variant in the ATM gene is predicted to introduce a premature translation termination codon, which is predicted to result in nonsense-mediated mRNA decay. This variant has an extremely low frequency in large databases of genetic variation in the general population. This variant has been reported in multiple patients with Ataxia-telangiectasia (PMID 10425038, 15843990, 16266405 and 25614872). Experimental studies in heterozygous cell lines suggested that this variant leads to reduced ATM protein expression following exposure to radiation (PMID 14970866). Bi-allelic variants in the ATM gene are associated with Ataxia-telangiectasia (MIM #208900). Therefore, the c.381delA (p.Val128*) variant in the ATM gene is classified as pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center RCV001262808 SCV001440814 pathogenic Familial cancer of breast 2019-01-01 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000478446 SCV001446824 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City RCV000627887 SCV001133023 pathogenic Ataxia-telangiectasia syndrome 2019-09-26 no assertion criteria provided clinical testing
Natera, Inc. RCV000627887 SCV001454831 pathogenic Ataxia-telangiectasia syndrome 2020-09-16 no assertion criteria provided clinical testing

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