Submissions for variant NM_000051.4(ATM):c.4396C>T (p.Arg1466Ter)

dbSNP: rs730881369

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000227538	SCV000282958	pathogenic	Ataxia-telangiectasia syndrome	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1466*) 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 (rs730881369, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (PMID: 10425038, 12552559, 19691550, 22213089, 22527104, 26439923). 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: 236716). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000445657	SCV000537651	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 29 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 4/251064 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.
Ambry Genetics	RCV000445657	SCV000581466	pathogenic	Hereditary cancer-predisposing syndrome	2024-02-01	criteria provided, single submitter	clinical testing	The p.R1466* pathogenic mutation (also known as c.4396C>T), located in coding exon 28 of the ATM gene, results from a C to T substitution at nucleotide position 4396. This changes the amino acid from an arginine to a stop codon within coding exon 28. This pathogenic mutation has been observed in numerous individuals with ataxia-telangiectasia (Castellví-Bel S et al. Hum. Mutat. 1999;14:156-62; Buzin CH et al. Hum. Mutat. 2003 Feb;21:123-31; Cavalieri S et al. Ann. Hum. Genet. 2008 Jan;72:10-8; Chessa L et al. Ann. Hum. Genet. 2009 Sep;73:532-9; Verhagen MM et al. Hum. Mutat., 2012 Mar;33:561-71; Chen Z et al. PLoS ONE, 2015 Oct;10:e0139738). It was also reported in an individual with bilateral breast cancer and a family history of breast cancer (Snape K et al. Breast Cancer Res. Treat. 2012 Jul;134:429-33) as well as in an individual diagnosed with breast carcinoma in situ at age 72 (Eliade M et al. Oncotarget, 2017 Jan;8:1957-1971). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000227538	SCV000694281	pathogenic	Ataxia-telangiectasia syndrome	2016-01-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000657608	SCV000779350	pathogenic	not provided	2020-02-26	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; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Observed in the heterozygous state in an individual with a personal and family history of breast cancer (Snape 2012); This variant is associated with the following publications: (PMID: 25525159, 10425038, 22527104, 12552559, 26439923, 18431795, 19691550, 11857346, 22213089, 32885271)
Counsyl	RCV000227538	SCV000795828	pathogenic	Ataxia-telangiectasia syndrome	2017-11-19	criteria provided, single submitter	clinical testing
Mendelics	RCV000227538	SCV000838539	pathogenic	Ataxia-telangiectasia syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000762821	SCV000893179	pathogenic	Familial cancer of breast; Ataxia-telangiectasia syndrome	2018-10-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000657608	SCV001249805	pathogenic	not provided	2019-07-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657608	SCV002774764	pathogenic	not provided	2021-07-13	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of ATM protein synthesis. In addition, it has been reported in individuals affected with ataxia-telangiectasia in the published literature (PMIDs: 26439923 (2015), 22527104 (2012), 22213089 (2011), 19691550 (2009), 12552559 (2003), and 10425038 (1999)). Based on the available information, this variant is classified as pathogenic.
Baylor Genetics	RCV003463629	SCV004207089	pathogenic	Familial cancer of breast	2023-10-02	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003463629	SCV004930989	pathogenic	Familial cancer of breast	2024-01-24	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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356094	SCV001551162	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Arg1466* variant was identified in 10 of 1670 proband chromosomes (frequency: 0.006) from individuals or families with ataxia-telangiectasia or breast cancer (Buzin 2003, Castellví Bel 1999, Chen 2015, Chessa 2009, Eliade 2017, Verhagen 2011). The variant was also identified in dbSNP (ID: rs730881369) as "With Pathogenic, Uncertain significance allele", ClinVar (classified as pathogenic by Invitae, Ambry Genetics, GeneDx and four other submitters), and in LOVD 3.0 (2x). The variant was identified in control databases in 4 of 245856 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 1 of 33544 chromosomes (freq: 0.00003), European in 1 of 111498 chromosomes (freq: 0.000009), and South Asian in 2 of 30750 chromosomes (freq: 0.00007); it was not observed in the African, Other, Ashkenazi Jewish, East Asian, or Finnish populations. The c.4396C>T variant leads to a premature stop codon at position 1466, 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 ATM-associated cancer susceptibility and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Laboratory for Genotyping Development, RIKEN	RCV003165589	SCV002758094	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research