ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7096G>T (p.Glu2366Ter) (rs587781672)

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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 RCV000129830 SCV000184646 pathogenic Hereditary cancer-predisposing syndrome 2017-07-10 criteria provided, single submitter clinical testing The p.E2366* <span style="font-family:arial,sans-serif; font-size:10pt">pathogenic mutation (also known as c.7096G>T) located in coding exon 48 of the ATM gene, results from a G to T substitution at nucleotide position 7096. This changes the amino acid from a glutamic acid to a stop codon within coding exon 48. This mutation was previously identified in an individual with ataxia-telangectasia using a protein truncation assay (Du L et al. Mutat. Res. 2008; 640:139-44). This mutation was also identified in one out of a series of 144 Polish patients with hereditary breast cancer (Cybulski C et al. Clin. Genet., 2015 Oct;88:366-70). 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 RCV000169152 SCV000220379 likely pathogenic Ataxia-telangiectasia syndrome 2014-06-05 criteria provided, single submitter literature only
Invitae RCV000169152 SCV000829074 pathogenic Ataxia-telangiectasia syndrome 2020-10-21 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu2366*) 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 reported in an individual affected with ataxia-telangiectasia (PMID: 18321536). Additionally, the variant has been reported in an individual affected with hereditary breast cancer (PMID: 25330149). ClinVar contains an entry for this variant (Variation ID: 141344). 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 RCV000169152 SCV000918577 pathogenic Ataxia-telangiectasia syndrome 2018-11-23 criteria provided, single submitter clinical testing Variant summary: ATM c.7096G>T (p.Glu2366X) 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 4.1e-06 in 246208 control chromosomes. c.7096G>T has been reported in the literature in a compound heterozygous individual affected with Ataxia-Telangiectasia (Du 2008) and in a heterozygous individual affected with Breast Cancer (Cybulski 2015). At least two publications reported experimental evidence evaluating an impact on protein function, demonstrating the lack of protein, no ATM-dependent kinase activity and increased radiosensitivity in a patient derived lymphoblastoid cell line that carried the variant together with another truncating ATM variant (Du 2013, Nakamura 2014). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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