ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.6997dup (rs587781299)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129007 SCV000172903 pathogenic Hereditary cancer-predisposing syndrome 2018-10-04 criteria provided, single submitter clinical testing The c.6997dupA pathogenic mutation, located in coding exon 47 of the ATM gene, results from a duplication of A at nucleotide position 6997, causing a translational frameshift with a predicted alternate stop codon (p.T2333Nfs*40). This mutation has been reported in multiple individuals with ataxia-telangiectasia (Stankovic T et al. Am. J. Hum. Genet. 1998 Feb;62:334-45; Li A et al. Am. J. Med. Genet. 2000 May;92:170-7; Exley AR et al. Clin. Immunol. 2011 Jul;140:26-36). It has also been reported patients with personal and/or family histories of early onset breast cancer (Goldgar DE et al. Breast Cancer Res. 2011 Jul;13:R73; Maxwell KN et al. Am. J. Hum. Genet. 2016 May;98:801-17; Tung N et al. Cancer, 2015 Jan;121:25-33). 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 RCV000205392 SCV000260039 pathogenic Ataxia-telangiectasia syndrome 2020-10-21 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Thr2333Asnfs*40) in the ATM gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual with ataxia-telangiectasia (PMID: 9463314), and in several individuals affected with breast cancer (PMID: 21787400, 26845104). It has also been reported in an individual with colorectal cancer (PMID: 23585368). It is also known as 6996_6997insA in the literature. ClinVar contains an entry for this variant (Variation ID: 140818). Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). For these reasons, this variant has been classified as Pathogenic.
University of Washington Department of Laboratory Medicine, University of Washington RCV000129007 SCV000266020 pathogenic Hereditary cancer-predisposing syndrome 2015-11-20 criteria provided, single submitter clinical testing
GeneDx RCV000236518 SCV000292478 pathogenic not provided 2018-08-22 criteria provided, single submitter clinical testing This duplication of one nucleotide in ATM is denoted c.6997dupA at the cDNA level and p.Thr2333AsnfsX40 (T2333NfsX40) at the protein level. The normal sequence, with the base that is duplicated in brackets, is ACTT[dupA]CATA. The duplication causes a frameshift, which changes a Threonine to an Asparagine at codon 2333, and creates a premature stop codon at position 40 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. ATM c.6997dupA, previously reported as 6997insA, has been observed in association with breast cancer, colorectal cancer, and Ataxia-telangiectasia (Stankovic 1998, Thompson 2005, Goldgar 2011, Smith 2013). We consider this variant to be pathogenic.
Counsyl RCV000205392 SCV000678163 likely pathogenic Ataxia-telangiectasia syndrome 2015-08-25 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129007 SCV000682383 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000205392 SCV000916577 pathogenic Ataxia-telangiectasia syndrome 2018-06-04 criteria provided, single submitter clinical testing Variant summary: ATM c.6997dupA (p.Thr2333AsnfsX40) 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. The variant allele was found at a frequency of 8.1e-06 in 245820 control chromosomes. c.6997dupA has been reported in the literature in individuals affected with Ataxia-Telangiectasia (Stankovic 1998, Li 2000, Exley 2011). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, demonstrating the lack of ATM protein and ATM kinase activity in LCLs derived from a patient who had the variant of interest in compound heterozygosity with an other truncating ATM variant (Exley 2011). 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 (5x) or likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic.
Blueprint Genetics RCV000236518 SCV000927694 pathogenic not provided 2018-05-21 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000236518 SCV001475569 pathogenic not provided 2020-03-18 criteria provided, single submitter clinical testing The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity.

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