Submissions for variant NM_000051.4(ATM):c.4735C>T (p.Gln1579Ter)

dbSNP: rs869312755

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
University of Washington Department of Laboratory Medicine, University of Washington	RCV000210197	SCV000266017	likely pathogenic	Hereditary cancer-predisposing syndrome	2015-11-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000210197	SCV000273529	pathogenic	Hereditary cancer-predisposing syndrome	2021-05-24	criteria provided, single submitter	clinical testing	The p.Q1579* pathogenic mutation (also known as c.4735C>T), located in coding exon 30 of the ATM gene, results from a C to T substitution at nucleotide position 4735. This changes the amino acid from a glutamine to a stop codon within coding exon 30. This mutation has been reported in an individual with ataxia-telangiectasia, who also carried a second ATM mutation (Hoche F et al. Pediatr. Neurol. 2014 Sep;51:297-310). It was also identified in a patient with a personal history of breast cancer and a family history of ovarian cancer (Shirts BH et al. Genet. Med. 2016 Oct;18:974-81). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000234068	SCV000282966	pathogenic	Ataxia-telangiectasia syndrome	2023-09-08	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 224518). This premature translational stop signal has been observed in individual(s) with breast cancer and ataxia telangiectasia (PMID: 25037873, 26845104). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln1579*) 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).
GeneDx	RCV000255389	SCV000322058	pathogenic	not provided	2017-08-25	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.4735C>T at the cDNA level and p.Gln1579Ter (Q1579X) 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 with a second ATM pathogenic variant in at least one individual with ataxia telangiectasia (R?be 2010, Hoche 2014), and in a woman with breast cancer and a family history of ovarian cancer (Shirts 2016). We consider this variant to be pathogenic.
Counsyl	RCV000234068	SCV000678088	likely pathogenic	Ataxia-telangiectasia syndrome	2016-12-14	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000255389	SCV000692733	likely pathogenic	not provided	2017-11-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000234068	SCV000807210	pathogenic	Ataxia-telangiectasia syndrome	2017-09-01	criteria provided, single submitter	clinical testing	This nonsense mutation is categorized as deleterious according to ACMG guidelines (PMID:18414213). It was found twice in our laboratory in trans with a deleterious frameshift mutation in a set of affected siblings. 9-year-old female & 12-year-old male sibs had cerebellar ataxia, oculomotor apraxia, intellectual disability, hypertonia, spasticity, peripheral neuropathy, pigmentary skin changes.
Color Diagnostics, LLC DBA Color Health	RCV000210197	SCV000913947	pathogenic	Hereditary cancer-predisposing syndrome	2020-10-27	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 31 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: 26845104) and in the compound heterozygous state with a second ATM mutation in an individual affected with ataxia telangiectasia (PMID: 25037873). 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	RCV000234068	SCV002018918	pathogenic	Ataxia-telangiectasia syndrome	2019-02-25	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV004020572	SCV004932870	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.