ClinVar Miner

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

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129576 SCV000184358 pathogenic Hereditary cancer-predisposing syndrome 2019-06-07 criteria provided, single submitter clinical testing Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Deficient protein function in appropriate functional assay(s)
Counsyl RCV000169059 SCV000220222 likely pathogenic Ataxia-telangiectasia syndrome 2014-04-03 criteria provided, single submitter literature only
GeneDx RCV000215085 SCV000278817 pathogenic not provided 2018-11-26 criteria provided, single submitter clinical testing This pathogenic variant is denoted ATM c.2921+1G>A or IVS19+1G>A and consists of a G>A nucleotide substitution at the +1 position of intron 19 of the ATM gene. The variant, also reported as IVS21+1G>A using alternate nomenclature and exon numbering, destroys a canonical splice donor site and has been shown to result in exonic skipping, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product (Garcia-Perez 2001). This variant has been reported in patients with classic ataxia-telangiectasia in both the homozygous and compound heterozygous states and in at least one individual with endometrial cancer (Gilad 1996, Garcia-Perez 2001, Mitui 2003, Jeddane 2013, Ring 2016). We consider this variant to be pathogenic.
Color RCV000129576 SCV000537641 pathogenic Hereditary cancer-predisposing syndrome 2015-01-19 criteria provided, single submitter clinical testing
Invitae RCV000169059 SCV000546716 pathogenic Ataxia-telangiectasia syndrome 2020-01-07 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 present in population databases (rs587781558, ExAC 0.01%). This variant has been observed in individual(s) with ataxia-telangiectasia (PMID: 8845835, 11298136, 12815592, 23322442, 12673797). In two individuals this variant was found in the homozygous state, while in four individuals it was found as compound heterozygous with a second pathogenic ATM variant. It is also known as IVS21+1G>A and 2839del83 in the literature. ClinVar contains an entry for this variant (Variation ID: 141182). 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000507017 SCV000602557 pathogenic not specified 2016-08-29 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000169059 SCV000694238 pathogenic Ataxia-telangiectasia syndrome 2017-01-19 criteria provided, single submitter clinical testing Variant summary: The ATM c.2921+1G>A variant involves the alteration of a conserved intronic nucleotide, which 4/5 splice prediction tools predict a significant impact on normal splicing and ESE finder predicts the removal of an ESE binding site. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 3/121072 (1/40355), which does not exceed the estimated maximal expected allele frequency for a pathogenic ATM variant of 1/252 for Ataxia-Telangiectasia. Multiple publications cite the variant in A-T patients that were homozygous or compound heterozygous. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000762820 SCV000893178 pathogenic Familial cancer of breast; Ataxia-telangiectasia syndrome 2018-10-31 criteria provided, single submitter clinical testing
Research and Development,Genoox RCV000215085 SCV000916301 pathogenic not provided no assertion criteria provided clinical testing

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