ClinVar Miner

Submissions for variant NM_001351834.2(ATM):c.3707_3711TTATT[1] (p.Leu1238fs) (rs786201675)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164077 SCV000214687 pathogenic Hereditary cancer-predisposing syndrome 2018-08-28 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense);Strong segregation with disease (lod >3 = >10 meioses);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
University of Washington Department of Laboratory Medicine, University of Washington RCV000164077 SCV000266016 likely pathogenic Hereditary cancer-predisposing syndrome 2015-11-20 criteria provided, single submitter clinical testing
GeneDx RCV000222105 SCV000278822 pathogenic not provided 2017-10-04 criteria provided, single submitter clinical testing This deletion of five nucleotides in ATM is denoted c.3712_3716delTTATT at the cDNA level and p.Leu1238LysfsX6 (L1238KfsX6) at the protein level. The normal sequence, with the bases that are deleted in brackets, is TATT[delTTATT]AAAC. The deletion causes a frameshift, which changes a Leucine to a Lysine at codon 1238, and creates a premature stop codon at position 6 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.3712_3716delTTATT, also reported as ATM 3711del5, has been observed in the homozygous or compound heterozygous state with a second ATM variant in individuals with Ataxia-telangiectasia (Broeks 1998, Mitui 2003, Jacquemin 2012, Carranza 2017). We consider this variant to be pathogenic.
Invitae RCV000459956 SCV000546745 pathogenic Ataxia-telangiectasia syndrome 2019-12-03 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu1238Lysfs*6) 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 several unrelated individuals affected with ataxia-telangiectasia (PMID: 21665257, 22071889, 27528516). This variant has also been reported in an individual affected with chronic lymphocytic leukemia (PMID: 21933854), and an individual affected with bladder cancer, sarcoma, and polyposis (PMID: 26845104). ClinVar contains an entry for this variant (Variation ID: 184764). Loss-of-function variants in ATM are known to be pathogenic (PMID: 25614872, 23807571). For these reasons, this variant has been classified as Pathogenic.
Color RCV000164077 SCV000904683 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000459956 SCV000916544 pathogenic Ataxia-telangiectasia syndrome 2017-10-30 criteria provided, single submitter clinical testing Variant summary: The ATM c.3712_3716delTTATT (p.Leu1238LysfsX6) variant results in a premature termination codon, predicted to cause a truncated or absent ATM protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant is absent in 241134 control chromosomes (gnomAD). Multiple publications have cited the variant in homozygote and compound heterozygote A-T pts. In addition, multiple clinical diagnostic laboratories classified this variant as "likely pathogenic/pathogenic." Taken together, this variant is classified as pathogenic.

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