ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.5497-2A>G (rs786203796)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000167256 SCV000218097 pathogenic Hereditary cancer-predisposing syndrome 2020-01-16 criteria provided, single submitter clinical testing The c.5497-2A>G pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 36 in the ATM gene. An alteration impacting the same nucleotide position has been reported in a patient with ataxia-telangiectasia (AT) (Teraoka et al. Am. J. Hum. Genet. 1999 Jun;64(6):1617-31). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, the c.5497-2A>G variant is predicted to abolish the native acceptor splice 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.
Color Health, Inc RCV000167256 SCV000687624 likely pathogenic Hereditary cancer-predisposing syndrome 2019-04-10 criteria provided, single submitter clinical testing
Invitae RCV000627890 SCV000748774 likely pathogenic Ataxia-telangiectasia syndrome 2020-01-31 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 36 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 not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 187521). 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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