ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2921+1G>C (rs587781558)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000167947 SCV000218595 pathogenic Ataxia-telangiectasia syndrome 2020-07-14 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 19 of the ATM gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with an ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 188097). A different nucleotide change at this position, c.2921+1G>A, has been reported in individuals affected with ataxia-telangiectasia both in the homozygous state and as compound heterozygous with a second pathogenic ATM variant (PMID: 8845835, 11298136, 12815592, 23322442). The G>A sequence change has been reported to lead to aberrant splicing and exon skipping (PMID: 8845835). These data indicate that this nucleotide is crucial for normal RNA splicing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000217319 SCV000277701 pathogenic Hereditary cancer-predisposing syndrome 2019-10-01 criteria provided, single submitter clinical testing The c.2921+1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide after coding exon 18 of the ATM gene. A similar alteration, c.2921+1G>A (also designated as IVS21+1G>A in the literature), has been identified in a heterozygous state in multiple individuals with ataxia telangiectasia (A-T) and was shown to result in exon skipping (Gilad S et al, Hum. Mol. Genet. 1996 Apr; 5(4):433-9; García-Pérez MA et al, Clin. Exp. Immunol. 2001 Mar; 123(3):472-80; Castellvi-Bel et al. Hum. Mutat.1999;14(2):156-62; Mitui M et al. Hum. Mutat. 2003 Jul;22(1):43-50; Jeddane L et al. Neuromolecular Med. 2013 Jun;15(2):288-94). The c.2921+1G>C nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx RCV000236109 SCV000293826 pathogenic not provided 2016-11-21 criteria provided, single submitter clinical testing This variant is denoted ATM c.2921+1G>C or IVS19+1G>C and consists of a G>C nucleotide substitution at the +1 position of intron 19 of the ATM gene. This variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. Although c.2921+1G>C has not, to our knowledge, been published in the literature, another nucleotide change at this position, c.2921+1G>A, has been reported in multiple cases of classical Ataxia-telangiectasia and resulted in complete loss of the adjacent exon (Gilad 1996, García-Pérez 2001, Mitui 2003). Based on the current evidence, we consider ATM c.2921+1G>C to be pathogenic.
Color Health, Inc RCV000217319 SCV000682088 likely pathogenic Hereditary cancer-predisposing syndrome 2019-08-15 criteria provided, single submitter clinical testing
Counsyl RCV000167947 SCV000795509 likely pathogenic Ataxia-telangiectasia syndrome 2017-11-08 criteria provided, single submitter clinical testing
Department of Pediatric Oncology, Hematology and Clinical Immunology,University Clinics Duesseldorf RCV000217319 SCV001482291 pathogenic Hereditary cancer-predisposing syndrome criteria provided, single submitter research

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