Submissions for variant NM_000051.4(ATM):c.9019G>T (p.Glu3007Ter)

dbSNP: rs876660382

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000222768	SCV000277771	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-01	criteria provided, single submitter	clinical testing	The p.E3007* pathogenic mutation (also known as c.9019G>T), located in coding exon 62 of the ATM gene, results from a G to T substitution at nucleotide position 9019. This changes the amino acid from a glutamic acid to a stop codon within coding exon 62. This alteration occurs at the 3' terminus of theATM gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 50 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 alteration has been reported in a compound heterozygous state in a Dutch individual with ataxia telangiectasia (Broeks A et al. Hum. Mutat. 1998;12:330-7). This alteration has also been reported in a breast cancer patient undergoing multi-gene panel testing (Tung N et al. Cancer. 2015 Jan 1;121(1):25-33), in 1/535 pancreatic ductal adenocarcinoma patients (Zimmermann MT et al. Front Oncol, 2021 Mar;11:606820), and in 1/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med, 2018 04;7:1349-1358). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000233073	SCV000283103	pathogenic	Ataxia-telangiectasia syndrome	2023-04-01	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the ATM protein in which other variant(s) (p.Arg3047*) have been determined to be pathogenic (PMID: 8755918, 10980530, 18560558, 19431188, 19691550, 26628246). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). ClinVar contains an entry for this variant (Variation ID: 233403). This premature translational stop signal has been observed in individual(s) with breast cancer and ataxia-telangiectasia (PMID: 9792409, 25186627). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu3007*) in the ATM gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 50 amino acid(s) of the ATM protein.
GeneDx	RCV000255661	SCV000322216	likely pathogenic	not provided	2018-08-06	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.9019G>T at the cDNA level and p.Glu3007Ter (E3007X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamic Acid to a premature stop codon (GAA>TAA), and is predicted to cause loss of normal protein function through protein truncation. Due to the position of the variant, nonsense mediated decay is not expected to occur, but it is predicted to cause loss of normal protein function through protein truncation as the last 49 amino acids are no longer translated. The disrupted region at the end of the gene is located within the FATC domain (Stracker 2013). This variant has been reported in an individual with Ataxia-telangiectasia and in at least two individuals with breast cancer (Broeks 1998, Tung 2015, Hauke 2018). We consider ATM Glu3007Ter to be a likely pathogenic variant.
Color Diagnostics, LLC DBA Color Health	RCV000222768	SCV001340249	pathogenic	Hereditary cancer-predisposing syndrome	2021-04-27	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 63 of the ATM gene, creating a premature translation stop signal in the last coding exon. While this mutant transcript is predicted to escape the nonsense-mediated decay and be expressed as a truncated protein, this C-terminally truncated protein is expected to disrupt the TP53 binding domain and FATC domain and to affect normal ATM protein function (PMID: 19779456). In addition, a truncating variant (p.Arg3047*) occurring downstream of this variant is known to be disease-causing (ClinVar variation ID: 3029), suggesting that the truncated region is important for protein structure and function. This variant has been reported in an individual affected with ataxia telangiectasia (PMID: 9792409). This variant has also been reported in individuals affected with breast cancer (PMID: 25186627, 29522266). This variant has not been identified 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.
Revvity Omics, Revvity	RCV000233073	SCV002024404	likely pathogenic	Ataxia-telangiectasia syndrome	2019-04-29	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV004020686	SCV004931128	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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000255661	SCV001741557	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000255661	SCV001807334	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000255661	SCV001906245	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000255661	SCV001951856	pathogenic	not provided		no assertion criteria provided	clinical testing
Michigan Center for Translational Pathology, University of Michigan	RCV001854694	SCV002107489	pathogenic	Clear cell carcinoma of kidney	2022-03-23	no assertion criteria provided	clinical testing	ATM c.9019G>T; p.E3007* noted in a 36 year old female with aggressive, metastatic RCC and a significant family history of cancer (including father diagnosed with RCC at age 59, who died of rapidly progressive disease) with the tumor showing somatic loss of heterozygosity (LOH) by uniparental disomy. The substitution in ATM induces a nonsense variant, which truncates the final 49 amino acid residues from the C-terminal, expected to disrupt the TP53 binding domain and FATC domain and to affect normal ATM protein function (PMID: 19779456). Ataxia telangiectasia mutated gene (ATM) plays a critical role in DNA repair and response to double strand breaks. ATM is associated with increased risk of breast cancer, pancreatic cancer and prostate cancer.