ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.7886_7890del (p.Ile2629fs) (rs1450394308)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000222650 SCV000273655 pathogenic Hereditary cancer-predisposing syndrome 2018-10-04 criteria provided, single submitter clinical testing The c.7886_7890delTATTA pathogenic mutation, located in coding exon 52 of the ATM gene, results from a deletion of 5 nucleotides at nucleotide positions 7886 to 7890, causing a translational frameshift with a predicted alternate stop codon (p.I2629Sfs*25). This pathogenic mutation has been reported in a family with two cases of breast cancer under age 50 and one individual with ataxia-telangiectasia (Goldgar DE et al. Breast Cancer Res. 2011 Jul;13:R73). This mutation has also been reported in a compound heterozygous state with another alteration in ATM [c.6154G>A (p.E2052K)] in an individual with cervical dopa-responsive dystonia (DRD) (Charlesworth G et al. Neurology. 2013 Sep;81:1148-51). This alteration has been detected in 1/4112 breast cancer patients and 0/2399 healthy control individuals across numerous studies (Tavtigian S et al. Am. J. Hum. Genet. 2009 Oct;85:427-46). 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.
Counsyl RCV000003171 SCV000486550 pathogenic Ataxia-telangiectasia syndrome 2016-10-19 criteria provided, single submitter clinical testing
Invitae RCV000003171 SCV000547031 pathogenic Ataxia-telangiectasia syndrome 2020-10-08 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ile2629Serfs*25) 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 the literature as homozygous or compound heterozygous in individuals with ataxia-telangiectasia (PMID: 12815592, 23322442, 8845835, 23946315, 9600235). This variant has also been reported in individuals with breast cancer and/or ovarian cancer (PMID: 21787400, 26436112). This variant is also known as 7883del5, 7884_7888del5, c.7878_7882delTTATA and c.7886_7890del in the literature. ClinVar contains an entry for this variant (Variation ID: 230200). Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000483952 SCV000568334 pathogenic not provided 2018-10-22 criteria provided, single submitter clinical testing This deletion of five nucleotides in ATM is denoted c.7886_7890delTATTA at the cDNA level and p.Ile2629SerfsX25 (I2629SfsX25) at the protein level. The normal sequence, with the bases that are deleted in brackets, is ATTA[delTATTA]GCAA. The deletion causes a frameshift which changes an Isoleucine to a Serine at codon 2629, and creates a premature stop codon at position 25 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.7886_7890delTATTA, previously reported as 7883del5, 7884_7888del5, 7878del5, and 7886_7889del5, has been observed in both the homozygous and compound heterozygous state in patients with Ataxia-telangiectasia and in at least one individual with breast cancer (Gilad 1996, Ejima 1998, Mitui 2003, Exley 2011, Goldgar 2011, Charlesworth 2013, Jeddane 2013). We consider this variant to be pathogenic.
Color Health, Inc RCV000222650 SCV000682440 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000003171 SCV000694361 pathogenic Ataxia-telangiectasia syndrome 2017-05-25 criteria provided, single submitter clinical testing Variant summary: The ATM c.7886_7890delTATTA (p.Ile2629Serfs) variant (also known as 7878del5, 7883del5 and 7884_7888del5) results in a premature termination codon, predicted to cause a truncated or absent ATM 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 (e.g. p.Lys2756X, p.Arg2763X, p.Arg2993X, etc.). This variant is absent in 120872 control chromosomes from ExAC. This variant has been reported in several A-T patients/families across multiple countries in homozygous state as well as in compound heterozygous state with other pathogenic/likely pathogenic variants (Gilad_1996, Telatar_1996, Sasaki_1998, Stankovic_1998, Exley_2011, Mitui_2003, Jeddane_2013, Charlesworth_2013). Cosegregation of this variant with disease have also been reported from a family (Charlesworth_2013). It has also been found in a breast cancer patient (Hirotsu_2015), which is consistent with the fact that pathogenic variants in ATM gene are known to confer elevated risk of breast cancer in a heterozygous state. In a compound heterozygous patient that carried this variant and 3802delG, no ATM kinase activity and ATM protein expression was observed in lymphoblastoid cell line derived from the patient, strongly supporting its predicted outcome (Exley_2011). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Mendelics RCV000003171 SCV000838601 pathogenic Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
Cancer Genomics Group,Japanese Foundation For Cancer Research RCV001030602 SCV001193487 likely pathogenic Hereditary breast and ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research
OMIM RCV000003171 SCV000023329 pathogenic Ataxia-telangiectasia syndrome 1998-04-01 no assertion criteria provided literature only
GeneReviews RCV000003171 SCV000328270 pathogenic Ataxia-telangiectasia syndrome 2016-10-27 no assertion criteria provided literature only
GeneReviews RCV000003171 SCV000328287 pathogenic Ataxia-telangiectasia syndrome 2016-10-27 no assertion criteria provided literature only
Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute,Kanazawa Medical University RCV000003171 SCV001364283 pathogenic Ataxia-telangiectasia syndrome 2020-06-19 no assertion criteria provided clinical testing

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