ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.756_757del (p.Cys252_Glu253delinsTer) (rs876659003)

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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 RCV000222737 SCV000274943 pathogenic Hereditary cancer-predisposing syndrome 2020-02-14 criteria provided, single submitter clinical testing The c.756_757delTG pathogenic mutation, located in coding exon 6 of the ATM gene, results from a deletion of two nucleotides at nucleotide positions 756 to 757, causing a translational frameshift with a predicted alternate stop codon (p.C252*). This alteration has been reported (labeled as 755delG) in the literature in an Italian ataxia telangiectasia (A-T) family (Gilad S et al, Hum. Mol. Genet. 1996 Apr; 5(4):433-9). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Counsyl RCV000409635 SCV000487283 likely pathogenic Ataxia-telangiectasia syndrome 2016-11-09 criteria provided, single submitter clinical testing
Invitae RCV000409635 SCV000749096 pathogenic Ataxia-telangiectasia syndrome 2020-08-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Cys252*) 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 in an individual affected with ataxia-telangiectasia (PMID: 8845835). This variant is also known as 755delGT in the literature. ClinVar contains an entry for this variant (Variation ID: 231178). Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000409635 SCV000916613 pathogenic Ataxia-telangiectasia syndrome 2018-12-24 criteria provided, single submitter clinical testing Variant summary: ATM c.756_757delTG (p.Cys252X) 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 (eg. c.1027_1030delGAAA/p.Glu343fsX2, c.1139_1142dupACAG/p.Ser381fsX27). The variant was absent in 245832 control chromosomes. c.756_757delTG has been reported in the literature in individuals affected with Ataxia-Telangiectasia (Gilad_996a, Sun_2002, Heinrich_2006, Prodosmo_2013). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence showing that this variant may lead to loss of protein expression (Sun_2002). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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