ClinVar Miner

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

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000521216 SCV000617369 pathogenic not provided 2017-05-25 criteria provided, single submitter clinical testing This deletion includes exons 9-10 of the CHEK2 gene. The genomic coordinates of this deletion spanat least chr22: 29,092,709-29,097,556 [hg19/GRCh37]. Using alternate nomenclature, this deletion is also publishedas CHEK2 del5395 or 5395del. CHEK2 deletion of exons 9-10 has been observed as a pathogenic Slavic foundervariant associated with familial breast and prostate cancer (Cybulski 2006, Walsh 2006, Foretova 2010). This deletionhas also been observed in multiple individuals with non-Hodgkin lymphoma or papillary thyroid cancer (Havranek 2015,Siolek 2015). Based on currently available evidence, we consider this deletion to be pathogenic
Invitae RCV000557758 SCV000622595 pathogenic Ataxia-telangiectasia syndrome 2020-09-17 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 been reported in an individual affected with ataxia-telangiectasia (PMID: 10330348). This variant is also known as IVS38-2A>C in the literature. ClinVar contains an entry for this variant (Variation ID: 449345). An experimental study has shown that this variant alters RNA splicing by utilizing a cryptic splice site in exon 37 that results in an out-of-frame deletion of 61 nucleotides (5497del61) (PMID: 10330348). This out-of-frame transcript is expected to result in an absent protein product due to nonsense-mediated decay. 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.
Ambry Genetics RCV000563654 SCV000660446 pathogenic Hereditary cancer-predisposing syndrome 2020-06-16 criteria provided, single submitter clinical testing The c.5497-2A>C intronic pathogenic mutation results from an A to C substitution two nucleotides upstream from coding exon 36 in the ATM gene. This mutation (designated as IVS38-2A>C) was reported in a patient with ataxia-telangiectasia (AT) (Teraoka et al. Am. J. Hum. Genet. 1999 Jun;64(6):1617-31). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. RNA analyses have shown that this alteration leads to aberrant splicing, resulting in a transcript that is predicted to undergo nonsense-mediated mRNA decay (Casadei S et al. Proc. Natl. Acad. Sci. U.S.A., 2019 Dec, Teraoka et al. Am. J. Hum. Genet. 1999 Jun;64(6):1617-31, Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Color Health, Inc RCV000563654 SCV000687623 pathogenic Hereditary cancer-predisposing syndrome 2015-03-03 criteria provided, single submitter clinical testing
Counsyl RCV000557758 SCV000796308 likely pathogenic Ataxia-telangiectasia syndrome 2017-12-11 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000521216 SCV001447234 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
King Laboratory,University of Washington RCV001171404 SCV001251308 pathogenic Familial cancer of breast 2019-09-01 no assertion criteria provided research

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