ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1139_1142dupACAG (p.Ser381Argfs) (rs886041340)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000493506 SCV000581441 pathogenic Hereditary cancer-predisposing syndrome 2018-03-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000285085 SCV000329804 likely pathogenic not provided 2016-07-18 criteria provided, single submitter clinical testing This duplication of four nucleotides in ATM is denoted c.1139_1142dupACAG at the cDNA level and p.Ser381ArgfsX27 (S381RfsX27) at the protein level. The normal sequence, with the bases that are duplicated in brackets, is GATT[dupACAG]TGTC. The duplication causes a frameshift which changes a Serine to an Arginine at codon 381, and creates a premature stop codon at position 27 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. ATM c.1139_1142dupACAG, published as c.1141insGACA using alternate nomenclature, has been observed in the compound heterozygous state in at least one patient with ataxia-telangiectasia (Hacia 1998). Based on the currently available information, we consider this duplication to be a likely pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000475637 SCV000694172 pathogenic Ataxia-telangiectasia syndrome 2016-08-24 criteria provided, single submitter clinical testing Variant summary: The ATM c.1139_1142dupACAG (p.Ser381Argfs) variant results in a premature termination codon, predicted to cause a truncated or absent ATM protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Trp393X, p.Gln1017X, p.Arg1466X, p.Tyr2755fs). One in silico tool predicts a damaging outcome for this variant. This variant was absent in 121144 control chromosomes, but has been cited in at least one AT patients in the literature. Taken together, this variant is classified as pathogenic.
Invitae RCV000475637 SCV000546710 pathogenic Ataxia-telangiectasia syndrome 2018-04-09 criteria provided, single submitter clinical testing This sequence change inserts 4 nucleotides in exon 9 of the ATM mRNA (c.1139_1142dupACAG), causing a frameshift at codon 381. This creates a premature translational stop signal (p.Ser381Argfs*27) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATM are known to be pathogenic. This particular variant has been reported in the compound heterozygous state in an individual affected with ataxia-telangiectasia (A-T) (PMID: 9872980). This variant is also known as 1141insGACA in the literature. For these reasons, this variant has been classified as Pathogenic.

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