ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3894dup (p.Ala1299fs) (rs587781823)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130103 SCV000184933 pathogenic Hereditary cancer-predisposing syndrome 2015-04-21 criteria provided, single submitter clinical testing
Color RCV000130103 SCV000905172 pathogenic Hereditary cancer-predisposing syndrome 2017-12-11 criteria provided, single submitter clinical testing
GeneDx RCV000342511 SCV000329805 pathogenic not provided 2017-06-27 criteria provided, single submitter clinical testing This duplication of one nucleotide in ATM is denoted c.3894dupT at the cDNA level and p.Ala1299CysfsX3 (A1299CfsX3) at the protein level. The normal sequence, with the base that is duplicated in braces, is ATTT[T]GCCT. The duplication causes a frameshift, which changes an Alanine to a Cysteine at codon 1299, and creates a premature stop codon at position 3 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.3894dupT, also known as ATM 3894insT and c.3894_3895insT, has been observed in the homozygous and compound heterozygous states in individuals with ataxia-telangiectasia (Teraoka 1999, Mitui 2003, Chessa 2009). Based on currently available evidence, we consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000231882 SCV000918564 pathogenic Ataxia-telangiectasia syndrome 2018-09-14 criteria provided, single submitter clinical testing Variant summary: ATM c.3894dupT (p.Ala1299CysfsX3) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 8.1e-06 in 246054 control chromosomes (gnomAD). c.3894dupT has been reported in the literature in multiple individuals affected with Ataxia-Telangiectasia (Chessa_2009, Micol_2011). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000231882 SCV000282945 pathogenic Ataxia-telangiectasia syndrome 2016-01-10 criteria provided, single submitter clinical testing This sequence change inserts 1 nucleotide in exon 26 of the ATM mRNA (c.3894dupT), causing a frameshift at codon 1299. This creates a premature translational stop signal (p.Ala1299Cysfs*3) and is expected to result in an absent or disrupted protein product. Truncating variants in ATM are known to be pathogenic. This particular truncation has been reported in individuals affected with AtaxiaTelangiectasia (PMID: 10330348, 12815592, 19691550). This variant is also known as c.3894_3895insT in the literature. For these reasons, this variant has been classified as Pathogenic.

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