ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.8977C>T (p.Arg2993Ter) (rs770641163)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 13
Download table as spreadsheet
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 The p.R2993* pathogenic mutation (also known as c.8977C>T), located in coding exon 61 of the ATM gene, results from a C to T substitution at nucleotide position 8977. This changes the amino acid from an arginine to a stop codon within coding exon 61. This mutation has been identified in multiple patients with ataxia-telangiectasia (A-T) from various ethnic backgrounds (Vorechovský I et al. Eur. J. Hum. Genet. 1996;4:352-5; Li A et al. Am. J. Med. Genet. 2000 May;92:170-7; Mitui M et al. Hum. Mutat. 2003 Jul;22:43-50; Magliozzi M et al. Dis. Markers 2006;22:257-64​; Jeddane L et al. Neuromolecular Med. 2013 Jun;15:288-94). In one study, the authors reported that ATM was not expressed in the cell line generated from a Spanish A-T patient who was compound heterozygous for this mutation and a second truncating mutation (Carranza D et al. Neuromolecular Med. 2017 Mar;19:161-174). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.
Counsyl RCV000169469 SCV000220908 likely pathogenic Ataxia-telangiectasia syndrome 2014-11-24 criteria provided, single submitter literature only
Invitae RCV000169469 SCV000283099 pathogenic Ataxia-telangiectasia syndrome 2020-10-19 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.
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.
Fulgent Genetics,Fulgent Genetics RCV000515430 SCV000611169 pathogenic Familial cancer of breast; Ataxia-telangiectasia syndrome 2017-05-18 criteria provided, single submitter clinical testing
Color Health, Inc RCV000165909 SCV000687865 pathogenic Hereditary cancer-predisposing syndrome 2020-12-21 criteria provided, single submitter clinical testing This variant changes 1 nucleotide in exon 62 of the ATM gene, creating a premature translation stop signal in the penultimate coding exon. This mutant transcript is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. While to our knowledge, functional studies have not been reported for this variant, it is expected to disrupt the TP53 binding and FATC domain (PMID: 19779456). This variant has been reported in the homozygous state or compound heterozygous state with a second ATM mutation in individuals affected with ataxia telangiectasia (PMID: 12815592, 16238588, 17124347, 20840352, 23322442, 30772474). This variant has also been reported in an individual affected with breast and/or ovarian cancer (PMID: 26898890). This variant has been identified in 3/251400 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
GeneKor MSA RCV000165909 SCV000821704 pathogenic Hereditary cancer-predisposing syndrome 2020-01-01 criteria provided, single submitter clinical testing This nonsense variant is a substitution of one nucleotide at position 8977 of the ATM protein, resulting in the creation of a stop codon at position 2993 of the ATM protein. The resulting protein is truncated and inactive. The mutation database ClinVar contains entries for this variant (Variation ID: 186330).
CeGaT Praxis fuer Humangenetik Tuebingen RCV000414034 SCV001246124 pathogenic not provided 2018-09-01 criteria provided, single submitter clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV001265579 SCV001443743 pathogenic Breast cancer, susceptibility to 2020-02-08 criteria provided, single submitter clinical testing This nonsense variant found in exon 62 of 63 is predicted to result in loss of normal protein function. This variant has been previously reported in the homozygous and compound heterozygous state in multiple individuals with Ataxia-Telangiectasia (PMID: 9043869, 12815592, 23322442, 17124347, 16238588, 20840352), and in the heterozygous state in individuals as part of cancer predisposition studies ( PMID: 21933854, 31159747, 28779002). This variant has been reported in the ClinVar database (Variation ID: 186330). Functional studies performed on cells derived from a patient with the c.8977C>T (p.Arg2993Ter) variant in the homozygous state and affected with Ataxia Telangiectasia showed loss of kinase activity (PMID: 23774824). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.001% (3/251400) and thus is presumed to be rare. In silico analyses support a deleterious effect of the c.8977C>T (p.Arg2993Ter) variant on protein function. Based on the available evidence, the c.8977C>T (p.Arg2993Ter) variant is classified as Pathogenic.
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
Natera, Inc. RCV000169469 SCV001452584 pathogenic Ataxia-telangiectasia syndrome 2020-09-16 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000414034 SCV001552427 likely pathogenic not provided no assertion criteria provided clinical testing The ATM p.Arg2993X variant was identified in 10 (1 homozygous) of 972 proband chromosomes (frequency: 0.01) from Italian, Spanish and British individuals or families with BRCA1/2 negative breast cancer, Ataxia-Telangiectasia or CLL; and was not identified in 2196 chromosomes from healthy individuals (Chessa 2009, Grana 2011, Magliozzi 2006 , Skowronska 2012, Mitui 2003). The variant was also identified in dbSNP (ID: rs770641163) “With Pathogenic allele”, ClinVar (classified as likely pathogenic by Counsyl,Dr. Peter K. Rogan Lab,Western University and pathogenic by Ambry Genetics, Invitae and GeneDx), Clinvitae (4x), and Cosmic (7x in thyroid, breast, large intestine and endometrial carcinomas and lymphoid neoplasm) and was not identified in the COGR. The variant was identified in control databases in 3 of 246160 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European Non-Finnish population in 3 of 111620 chromosomes (freq: 0.00003); it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.Arg2993X variant leads to a premature stop codon at position 2993 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the ATM gene are an established mechanism of disease in Ataxia-Telangiectasia and is the type of variant expected to cause the disorder; the relative risk for hereditary breast and ovarian cancer is not certain but may lead to increased risk of breast cancer. In addition, this variant occurs within 50 base pairs of the penultimate exon junction of the gene and stop codon or nonsense mutations in this region may not be subjected to nonsense mediated RNA decay, although further study would be required to validate this hypothesis and it is currently not possible to determine whether or not this might influence the severity of the disorder. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.

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.