Submissions for variant NM_000051.4(ATM):c.538C>T (p.Gln180Ter)

gnomAD frequency: 0.00003  dbSNP: rs730881333

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000505724	SCV000209675	pathogenic	not provided	2017-09-07	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.538C>T at the cDNA level and p.Gln180Ter (Q180X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in the compound heterozygous state in at least two patients with ataxia-telangiectasia (Heinrich 2006, Soukupova 2011), and in the heterozygous state in at least one patient with breast cancer (Frey 2017). This variant is considered pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000531127	SCV000622584	pathogenic	Ataxia-telangiectasia syndrome	2024-01-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln180*) 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 (rs730881333, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with breast cancer and ataxia-telangiectasia (PMID: 16411093, 26681312). ClinVar contains an entry for this variant (Variation ID: 181910). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV001024018	SCV001185970	pathogenic	Hereditary cancer-predisposing syndrome	2024-05-15	criteria provided, single submitter	clinical testing	The p.Q180* pathogenic mutation (also known as c.538C>T), located in coding exon 5 of the ATM gene, results from a C to T substitution at nucleotide position 538. This changes the amino acid from a glutamine to a stop codon within coding exon 5. This alteration has been previously described in two individuals with features of ataxia-telangectasia in conjunction with another ATM alteration; however, the phase of the alterations was not determined (Heinrich T et al. Eur. J. Pediatr., 2006 Apr;165:250-7; Soukupova J et al. Neuromolecular Med., 2011 Sep;13:204-11).This alteration was also identified in 1/10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel (Susswein LR et al. Genet. Med., 2016 08;18:823-32). 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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000505724	SCV001480082	pathogenic	not provided	2021-02-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001024018	SCV004356999	pathogenic	Hereditary cancer-predisposing syndrome	2023-09-05	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 6 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 reported in an individual affected with breast cancer (PMID: 26681312) and in the compound heterozygous state in at least two individuals affected with ataxia-telangiectasia (PMID: 16411093, 21833744). This variant has been identified in 1/31166 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.
Myriad Genetics, Inc.	RCV004019935	SCV004933942	pathogenic	Familial cancer of breast	2024-01-09	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.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000505724	SCV001906380	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000505724	SCV001953007	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000531127	SCV002094052	pathogenic	Ataxia-telangiectasia syndrome	2020-11-09	no assertion criteria provided	clinical testing