ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8876_8879del (p.Asp2959fs) (rs786204726)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169561 SCV000221056 likely pathogenic Ataxia-telangiectasia syndrome 2015-01-21 criteria provided, single submitter literature only
Invitae RCV000169561 SCV000283096 pathogenic Ataxia-telangiectasia syndrome 2018-01-02 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asp2959Glyfs*3) in the ATM gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs770704493, ExAC 0.009%). This This variant has been reported in individuals affected with ataxia-telangiectasia (PMID: 12815592). This variant is also known as 8875_8878delGACT and 8874_8877delTGAC in the literature. ClinVar contains an entry for this variant (Variation ID: 189140). Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000236349 SCV000293443 pathogenic not provided 2017-02-06 criteria provided, single submitter clinical testing This deletion of four nucleotides in ATM is denoted c.8876_8879delACTG at the cDNA level and p.Asp2959GlyfsX3 (D2959GfsX3) at the protein level. The normal sequence, with the bases that are deleted in brackets, is TTTG[delACTG]GACC. The deletion causes a frameshift which changes an Aspartic Acid to a Glycine at codon 2959, 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.8876_8879delACTG, also reported as c.8874_8877delTGAC using alternate nomenclature, has been reported in at least two individuals with Ataxia-telangiectasia (A-T), including once in the compound heterozygous state with an ATM nonsense variant and once in the homozygous state (Mitui 2003, Carranza 2016). In addition, a cell line derived from the homozygous A-T patient was evaluated, revealing the absence of ATM protein expression and intermediate radiosensitivity (Carranza 2016). Based on current evidence we consider ATM c.8876_8879delACTG to be pathogenic.
Ambry Genetics RCV000494628 SCV000581454 pathogenic Hereditary cancer-predisposing syndrome 2017-04-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Color RCV000494628 SCV000903724 pathogenic Hereditary cancer-predisposing syndrome 2018-03-09 criteria provided, single submitter clinical testing

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