ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.7705_7706del (p.Arg2568_Asp2569insTer) (rs759965045)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000204947 SCV000261175 pathogenic Ataxia-telangiectasia syndrome 2020-09-26 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asp2569*) in the ATM gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs759965045, ExAC 0.02%). This variant has been observed in individuals affected with ataxia-telangiectasia (PMID: 10330348, 10817650, 12815592). This variant is also known as 7705delGA and 7704_7705delAG in the literature. ClinVar contains an entry for this variant (Variation ID: 220550). Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000214581 SCV000275917 pathogenic Hereditary cancer-predisposing syndrome 2019-04-24 criteria provided, single submitter clinical testing The c.7705_7706delGA pathogenic mutation, located in coding exon 51 of the ATM gene, results from a deletion of two nucleotides at nucleotide positions 7705 to 7706, causing a translational frameshift with a predicted alternate stop codon (p.D2569*). This mutation has been identified in multiple families affected with ataxia-telangiectasia (A-T) (Li A and Swift M. Am. J. Med. Genet. 2000 May;92:170-7; Mitui M et al. Hum. Mutat. 2003 Jul;22:43-50). This mutation was also detected during the analysis of 49 cell lines derived from individuals with A-T (Teraoka S et al. Am J Hum Genet. 1999 Jun;64(6):1617-31). 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 RCV000204947 SCV000486046 likely pathogenic Ataxia-telangiectasia syndrome 2016-03-23 criteria provided, single submitter clinical testing
GeneDx RCV000478786 SCV000565939 pathogenic not provided 2018-06-14 criteria provided, single submitter clinical testing This deletion of two nucleotides is denoted ATM c.7705_7706delGA at the cDNA level and p.Asp2569Ter (D2569X) at the protein level. The normal sequence, with the bases that are deleted in brackets, is CAGA[delGA]TGAA. The deletion creates a nonsense variant, which changes an Aspartic Acid to a premature stop codon. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. ATM c.7705_7706delGA, also reported as 7705delGA and 7704_7705delAG, has been observed in several individuals with ataxia telangiectasia (Teraoka 1999, Li 2000, Mitui 2003), and is considered pathogenic.
Color Health, Inc RCV000214581 SCV000682432 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000204947 SCV000914480 likely pathogenic Ataxia-telangiectasia syndrome 2018-11-13 criteria provided, single submitter clinical testing The ATM c.7705_7706delGA (p.Asp2569Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. The p.Asp2569Ter variant has been reported in three studies in which it was found in three individuals with ataxia telangiectasia (AT) (Teraoka et al. 1999; Mitui et al. 2003; Li et al. 2000). The variant was found in a compound heterozygous state in one Spanish individual in trans with a splice site variant, in a presumed compound heterozygous state with no second variant identified in a lymphoblastoid cell line derived from a patient with AT and in one of 268 AT chromosomes from a study of AT families in the US and Canada. The variant has also been reported with unspecified zygosity in one individual diagnosed with gastric cancer (Slavin et al. 2017). Control data are unavailable for the p.Asp2569Ter variant which is reported at a frequency of 0.000149 in the Latino population of the Genome Aggregation Database. Based on the evidence and potential impact of stop-gained variants, the p.Asp2569Ter variant is classified as likely pathogenic for ataxia telangiectasia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000204947 SCV001478774 pathogenic Ataxia-telangiectasia syndrome 2021-01-11 criteria provided, single submitter clinical testing Variant summary: ATM c.7705_7706delGA (p.Asp2569X) 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. The variant allele was found at a frequency of 2e-05 in 251176 control chromosomes. c.7705_7706delGA has been reported in the literature in individuals affected with Ataxia-Telangiectasia and other types of cancers (Teraoka_1999, Mitui_2003, Li_2000, Lu_2015, etc). 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. Seven 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.
Natera, Inc. RCV000204947 SCV001462590 pathogenic Ataxia-telangiectasia syndrome 2020-09-16 no assertion criteria provided clinical testing

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