ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1158del (p.Lys387fs) (rs587782085)

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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 RCV000130585 SCV000185457 pathogenic Hereditary cancer-predisposing syndrome 2013-12-20 criteria provided, single submitter clinical testing
GeneDx RCV000486071 SCV000567547 pathogenic not provided 2015-08-04 criteria provided, single submitter clinical testing This deletion of one nucleotide in ATM is denoted c.1158delG at the cDNA level and p.Lys387ArgfsX3 (K387RfsX3) at the protein level. The normal sequence, with the base that is deleted in braces, is AAAG[G]AAGA. The deletion causes a frameshift, which changes a Lysine to an Arginine at codon 387, 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.1158delG has been reported in at least three patients with a clinical diagnosis of Ataxia telangiectasia (Izatt 1999, Thompson 2005). we consider this variant to be pathogenic. The presence of
Invitae RCV000703678 SCV000832591 pathogenic Ataxia-telangiectasia syndrome 2019-10-21 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Lys387Argfs*3) in the ATM gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with ataxia-telangiectasia (PMID: 10234507). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 141887). Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). For these reasons, this variant has been classified as Pathogenic.
Color RCV000130585 SCV000905167 pathogenic Hereditary cancer-predisposing syndrome 2020-05-13 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000703678 SCV001360471 pathogenic Ataxia-telangiectasia syndrome 2019-06-28 criteria provided, single submitter clinical testing Variant summary: ATM c.1158delG (p.Lys387ArgfsX3) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (c.1339C>T, p.Arg447X; c.1564_1565delGA, p.Glu522fsX43; c.2502dupA, p.Val835fsX7). The variant was absent in 251274 control chromosomes (gnomAD). The variant, c.1158delG, has been reported in the literature in multiple individuals affected with Ataxia-Telangiectasia (Izatt_1999, Thompson_2005, Nahas_2009, Schon_2019). These data indicate that the variant is 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 other clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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