Submissions for variant NM_000051.4(ATM):c.2806_2809dup (p.Glu937fs)

dbSNP: rs757237504

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479847	SCV000568318	pathogenic	not provided	2023-08-18	criteria provided, single submitter	clinical testing	Frameshift 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); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 9443866, 10330348, 12673797, 29922827, 32427313)
Ambry Genetics	RCV000567665	SCV000665316	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-07	criteria provided, single submitter	clinical testing	The c.2806_2809dupCTAG pathogenic mutation, located in coding exon 17 of the ATM gene, results from a duplication of CTAG at nucleotide position 2806, causing a translational frameshift with a predicted alternate stop codon (p.E937Afs*33). This mutation has been detected in an individual with ataxia-telangiectasia in conjunction with another pathogenic ATM mutation (Teraoka et al. Am. J. Hum. Genet. 1999 Jun;64(6):1617-31). 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 or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV000810916	SCV000951156	pathogenic	Ataxia-telangiectasia syndrome	2023-09-26	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu937Alafs*33) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (PMID: 9443866). This variant is also known as c.2810insCTAG. ClinVar contains an entry for this variant (Variation ID: 420010). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000810916	SCV002018929	pathogenic	Ataxia-telangiectasia syndrome	2019-06-27	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000479847	SCV002064365	pathogenic	not provided	2019-02-11	criteria provided, single submitter	clinical testing	This sequence change in the ATM gene is a 4 base pair duplication in exon 18, c.2806_2809dup. This sequence change results in an amino acid frameshift and creates a premature stop codon 32 amino acids downstream of the mutation, p.Glu937Alafs*33. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated ATM protein with potentially abnormal function. This pathogenic sequence change has previously been described in a patient with ataxia telangiectasia (Telatar et al., 1998). This sequence change was identified with another likely pathogenic ATM variant in a patient.
Fulgent Genetics, Fulgent Genetics	RCV002489154	SCV002783601	pathogenic	Familial cancer of breast; Ataxia-telangiectasia syndrome	2021-11-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000810916	SCV002819835	likely pathogenic	Ataxia-telangiectasia syndrome	2022-12-27	criteria provided, single submitter	clinical testing	Variant summary: ATM c.2806_2809dupCTAG (p.Glu937AlafsX33) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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. The variant was absent in 251396 control chromosomes. c.2806_2809dupCTAG has been reported in the literature in individuals affected with Ataxia-Telangiectasia (eg. Teraoka_1999, Telatar_1998). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV003470550	SCV004212011	pathogenic	Familial cancer of breast	2023-04-18	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003470550	SCV004931083	pathogenic	Familial cancer of breast	2024-01-18	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Natera, Inc.	RCV000810916	SCV001452052	pathogenic	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing