ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2251-10T>G (rs730881346)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000580644 SCV000682043 likely pathogenic Hereditary cancer-predisposing syndrome 2018-07-26 criteria provided, single submitter clinical testing
Counsyl RCV000161929 SCV000678106 likely pathogenic Ataxia-telangiectasia syndrome 2017-02-09 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515310 SCV000611162 likely pathogenic Familial cancer of breast; Ataxia-telangiectasia syndrome 2017-05-18 criteria provided, single submitter clinical testing
GeneDx RCV000159691 SCV000209697 likely pathogenic not provided 2019-01-18 criteria provided, single submitter clinical testing This variant is denoted ATM c.2251-10T>G or IVS14-10T>G and consists of a T>G nucleotide substitution at the -10 position of intron 14 of the ATM gene. This variant, previously referred to as IVS16-10T>G, has been reported in the compound heterozygous state in individuals with ataxia-telangiectasia and, consistent with in silico splicing models, has been shown to create a new splice acceptor site, which results in the addition of nine nucleotides and subsequently a truncated protein (Telatar 1998, Teraoka 1999, Becker-Catania 2000, Buzin 2003, Reiman 2011). Additionally, this variant has been observed in the heterozygous state in at least three individuals with breast cancer (Decker 2017). ATM c.2251-10T>G was not observed at a significant allele frequency in large population cohorts (Lek 2016). Based on currently available evidence, we consider ATM c.2251-10T>G to be a likely pathogenic variant.
Invitae RCV000161929 SCV000211913 pathogenic Ataxia-telangiectasia syndrome 2018-12-24 criteria provided, single submitter clinical testing This sequence change falls in intron 14 of the ATM gene. It does not directly change the encoded amino acid sequence of the ATM protein. This variant is present in population databases (rs730881346, ExAC 0.002%). This variant has been reported to co-occur with at least 3 different pathogenic ATM variants (c.2806_2809dupCTAG, p.Arg2832Cys, c.8786+1G>A) in individuals with ataxia-telangiectasia (PMID: 9443866, 10330348, 10873394, 9463314, 12552559). While it was not explicitly stated that the two ATM variants in these individuals were on opposite chromosomes, this observation suggests that the c.2251-10T>G substitution contributes to the cause of disease. It has also been observed as homozygous in individuals affected with ataxia-telangiectasia (PMID: 9463314), and as a heterozygous change in an individual with breast cancer (PMID: 26681312). This variant is also known as IVS16-10T>G and 2249ins9nt in the literature. ClinVar contains an entry for this variant (Variation ID: 181926). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant alters RNA splicing by creating a cryptic acceptor splice site 9 nucleotides upstream of the consensus acceptor splice site, leading to the use of a premature stop codon. This prediction is supported by experimental studies, although the data was not made available for review (PMID: 10330348). For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics RCV000159691 SCV000805513 pathogenic not provided 2016-01-20 criteria provided, single submitter clinical testing

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