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

dbSNP: rs770641163

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165909	SCV000216664	pathogenic	Hereditary cancer-predisposing syndrome	2021-04-15	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 alteration occurs at the 3' terminus of theATM gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 64 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). 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; Claret Teruel G et al. Pediatr Allergy Immunol, 2005 Nov;16:615-8; Magliozzi M et al. Dis. Markers 2006;22:257-64; Broccoletti T et al. Eur J Neurol, 2011 Apr;18:564-70; Jeddane L et al. Neuromolecular Med. 2013 Jun;15:288-94; Balta G et al. J Pediatr Hematol Oncol, 2019 04;41:243-246; Suspitsin E et al. Eur J Med Genet, 2020 Jan;63:103630). 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). Based on the supporting evidence, 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	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg2993*) in the ATM gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 64 amino acid(s) of the ATM protein. This variant is present in population databases (rs770641163, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with chronic lymphocytic leukemia and ataxia-telangiectasia (A-T) (PMID: 12815592, 16238588, 17124347, 20840352, 21933854, 23322442). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 186330). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects ATM function (PMID: 23774824). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000414034	SCV000490415	pathogenic	not provided	2022-05-13	criteria provided, single submitter	clinical testing	Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 64 amino acids are lost, and other loss-of-function variants have been reported downstream in ClinVar; Observed in both the homozygous and compound heterozygous states in multiple unrelated patients with ataxia telangiectasia (Li 2000, Sun 2002, Mitui 2003, Claret Teruel 2005, Magliozzi 2006, Chessa 2009, Carranza 2017); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23774824, 21445571, 24682267, 10817650, 25862857, 16238588, 19691550, 17124347, 26898890, 9043869, 21933854, 12673797, 17968022, 15498871, 19770270, 23322442, 24951259, 25344691, 12815592, 12072877, 26886021, 27664052, 29489040, 30339652, 28779002, 29915322, 31159747, 31549213, 30772474, 29625052, 33436325, 31285527, 23532176, 35245693, 35078243, 34949663)
Fulgent Genetics, Fulgent Genetics	RCV000515430	SCV000611169	pathogenic	Familial cancer of breast; Ataxia-telangiectasia syndrome	2021-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000165909	SCV000687865	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-02	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 lacking the C-terminal TP53 binding domain and FATC domain (PMID: 19779456). This variant has been reported in an individual affected with breast and/or ovarian cancer (PMID: 26898890). This variant has also been reported in the homozygous state or compound heterozygous state with a pathogenic variant in the same gene in individuals affected with autosomal recessive ataxia telangiectasia (PMID: 12815592, 16238588, 17124347, 20840352, 23322442, 30772474). 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 Center for Human Genetics Tuebingen	RCV000414034	SCV001246124	pathogenic	not provided	2023-08-01	criteria provided, single submitter	clinical testing	ATM: PVS1:Strong, PM2, PM3, PS3:Supporting, PS4:Supporting
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.
Revvity Omics, Revvity	RCV000169469	SCV002021973	pathogenic	Ataxia-telangiectasia syndrome	2020-12-10	criteria provided, single submitter	clinical testing
Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000414034	SCV002818267	pathogenic	not provided	2022-12-17	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003462193	SCV004207043	pathogenic	Familial cancer of breast	2023-10-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003462193	SCV004932962	pathogenic	Familial cancer of breast	2024-02-06	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Dr. Peter K. Rogan Lab, Western University	RCV000416708	SCV000262587	likely pathogenic	Hereditary breast 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.