Submissions for variant NM_000051.4(ATM):c.8545C>T (p.Arg2849Ter)

gnomAD frequency: 0.00001  dbSNP: rs587778080

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000478987	SCV000344844	pathogenic	not provided	2016-08-15	criteria provided, single submitter	clinical testing
GeneDx	RCV000478987	SCV000564671	pathogenic	not provided	2022-12-30	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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 23891399, 18634022, 29922827, 10425038, 24728327, 16266405, 17124347, 19691550, 31069529, 27083775, 32875559, 34153142, 32427313)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000407552	SCV000622826	pathogenic	Ataxia-telangiectasia syndrome	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg2849*) 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 (rs587778080, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia and gastrointestinal tumor (PMID: 10425038, 16266405, 17124347, 19691550, 27083775). ClinVar contains an entry for this variant (Variation ID: 133637). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000566641	SCV000665502	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-29	criteria provided, single submitter	clinical testing	The p.R2849* pathogenic mutation (also known as c.8545C>T), located in coding exon 57 of the ATM gene, results from a C to T substitution at nucleotide position 8545. This changes the amino acid from an arginine to a stop codon within coding exon 57. This mutation has been identified in multiple individuals of Polish or Italian ancestry with clinical diagnoses of ataxia-telangiectasia (Castellví-Bel S et al. Hum. Mutat. 1999;14(2):156-62; Mitui M et al. Ann. Hum. Genet. 2005 Nov;69(Pt 6):657-64; Chessa L et al. Ann. Hum. Genet. 2009 Sep;73(Pt 5):532-9). In addition, this mutation was also detected in an individual with an unspecified gastrointestinal cancer on a hereditary cancer panel (Seifert BA et al. Clin. Cancer Res., 2016 Aug;22:4087-4094). 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	RCV000566641	SCV000682494	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 58 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 1/251124 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	RCV000407552	SCV000694379	pathogenic	Ataxia-telangiectasia syndrome	2017-08-21	criteria provided, single submitter	clinical testing	Variant summary: The ATM c.8545C>T (p.Arg2849X) 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.8977C>T, p.Arg2993X). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 121276 control chromosomes and has been reported in multiple AT patients in the literature. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001258124	SCV001434997	pathogenic	Ataxia-telangiectasia syndrome; Breast cancer, susceptibility to	2019-06-17	criteria provided, single submitter	clinical testing	The c.8545C>T (p.Arg2849*) variant in the ATM gene creates a stop codon which is predicted to lead to nonsense-mediated mRNA decay. The variant has been reported in multiple patients with ataxia-telangiectasia (PMID 10425038,16266405, 17124347, 19691550) and in one individual with GI tract cancer (PMID 27083775). This variant is extremely rare in general population. Therefore, this c.8545C>T (p.Arg2849*) variant in the ATM gene is classified as pathogenic.
Institute of Human Genetics, University Hospital of Duesseldorf	RCV000407552	SCV004171156	pathogenic	Ataxia-telangiectasia syndrome		criteria provided, single submitter	not provided
Baylor Genetics	RCV003460846	SCV004208778	pathogenic	Familial cancer of breast	2024-03-17	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003460846	SCV004932924	pathogenic	Familial cancer of breast	2024-02-02	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.
ITMI	RCV000120162	SCV000084304	not provided	not specified	2013-09-19	no assertion provided	reference population
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino	RCV001352893	SCV001547496	likely pathogenic	Tip-toe gait	2021-01-26	flagged submission	clinical testing	We conducted a clinical examination of patients about toe walking. The ATM c.8545C>T was detected in one patient. We also examined a control group of children without toe walking (100 children). In this group this variant could not be identified. Gait disorder
Natera, Inc.	RCV000407552	SCV002082592	pathogenic	Ataxia-telangiectasia syndrome	2020-08-19	no assertion criteria provided	clinical testing