ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1898+2T>G (rs587782124)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130662 SCV000185548 pathogenic Hereditary cancer-predisposing syndrome 2016-04-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
CeGaT Praxis fuer Humangenetik Tuebingen RCV000235311 SCV000892002 likely pathogenic not provided 2018-09-30 criteria provided, single submitter clinical testing
Color RCV000130662 SCV000682012 pathogenic Hereditary cancer-predisposing syndrome 2015-01-17 criteria provided, single submitter clinical testing
GeneDx RCV000235311 SCV000293075 pathogenic not provided 2018-11-13 criteria provided, single submitter clinical testing This variant is denoted ATM c.1898+2T>G or IVS12+2T>G and consists of a T>G nucleotide substitution at the +2 position of intron 12 of the ATM gene. This variant destroys a canonical splice site and is predicted to cause abnormal gene splicing, leading to an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant, also reported as ATM IVS14+2T>G, has been reported in the compound heterozygous state in individuals with Ataxia-telangiectasia, one of whom also developed pancreatic cancer (Stankovic 1998, Mitui 2005, Verhagen 2007, Cavalieri 2008, Davis 2013). Cell lines from two of these individuals demonstrated radiosensitivity and absence of ATM protein expression and kinase activity (Mitui 2005, Driessen 2013). Based on currently available evidence, we consider this variant to be pathogenic.
Invitae RCV000461282 SCV000546808 pathogenic Ataxia-telangiectasia syndrome 2018-12-21 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 12 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). This variant has been observed in individuals affected with both classical and atypical ataxia-telangiectasia (A-T) (PMID: 9463314, 16266405, 23566627, 24090759), including an individual in whom a pathogenic variant was detected on the opposite chromosome (in trans) (PMID: 16266405). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. This variant has also been reported in an additional individual affected with breast cancer (PMID: 10677309). This variant is also known as IVS14+2T>G in the literature. ClinVar contains an entry for this variant (Variation ID: 141939). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). For these reasons, this variant has been classified as Pathogenic.

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