Submissions for variant NM_000051.4(ATM):c.1369C>T (p.Arg457Ter)

gnomAD frequency: 0.00001  dbSNP: rs749036865

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000205849	SCV000260212	pathogenic	Ataxia-telangiectasia syndrome	2023-11-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg457*) in the ATM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). This variant is present in population databases (rs749036865, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia, breast cancer, and/or pancreatic cancer. (PMID: 17910737, 25428789, 26098866, 31285527). ClinVar contains an entry for this variant (Variation ID: 219999). For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000205849	SCV000486954	pathogenic	Ataxia-telangiectasia syndrome	2016-09-12	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000493633	SCV000581476	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-28	criteria provided, single submitter	clinical testing	The p.R457* pathogenic mutation (also known as c.1369C>T), located in coding exon 9 of the ATM gene, results from a C to T substitution at nucleotide position 1369. This changes the amino acid from an arginine to a stop codon within coding exon 9. This alteration has been detected as compound heterozygous in conjunction with a second pathogenic ATM mutation in multiple patients with ataxia telangiectasia (A-T) (Cavalieri S et al. Ann. Hum. Genet. 2008 Jan;72:10-8; Micol R et al. J Allergy Clin Immunol. 2011 Aug;128(2):382-9.e1; Driessen GJ et al. J Allergy Clin Immunol. 2013 May;131(5):1367-75.e9; Hoche F et al. Pediatr. Neurol. 2014 Sep;51:297-310). It has also been detected as heterozygous in patients diagnosed with breast cancer, gastric cancer, and pancreatic cancer (Churpek JE et al. Breast Cancer Res Treat. 2015 Jan;149(1):31-9; Helgason H et al. Nat Genet. 2015 Aug;47(8):906-10; Dudley B et al. Cancer. 2018 Apr 15;124(8):1691-1700). 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.
Color Diagnostics, LLC DBA Color Health	RCV000493633	SCV000687305	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 10 of the ATM gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been identified in 3/282772 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.
Fulgent Genetics, Fulgent Genetics	RCV000762813	SCV000893171	pathogenic	Familial cancer of breast; Ataxia-telangiectasia syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001814115	SCV001755677	pathogenic	Abnormal central motor function	2021-07-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000205849	SCV001774526	pathogenic	Ataxia-telangiectasia syndrome	2021-07-26	criteria provided, single submitter	clinical testing	Variant summary: ATM c.1369C>T (p.Arg457X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251402 control chromosomes. c.1369C>T has been reported in the literature in multiple individuals affected with Ataxia-Telangiectasia (example, Cavalieri_2008, Helgason_2015) and a variety of other tumors such as breast (example, Churpek_2015, Walsh_2021), pancreatic (example, Dudley_2018, Hutchings_2019). Given the increased risk for malignancies that has been reported among carriers of ATM gene mutations, these data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV003322602	SCV004027788	pathogenic	Familial cancer of breast	2023-05-05	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS4_MOD,PM2_SUP
Baylor Genetics	RCV003322602	SCV004212086	pathogenic	Familial cancer of breast	2023-02-17	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003322602	SCV004933528	pathogenic	Familial cancer of breast	2024-01-16	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.
Natera, Inc.	RCV000205849	SCV001456891	pathogenic	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing