ClinVar Miner

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

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Total submissions: 7
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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 2020-03-12 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, 27664052). 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 2019-02-03 criteria provided, single submitter clinical testing The c.8876_8879delACTG pathogenic mutation, located in coding exon 61 of the ATM gene, results from a deletion of 4 nucleotides at nucleotide positions 8876 to 8879, causing a translational frameshift with a predicted alternate stop codon (p.D2959Gfs*3). This mutation has been previously identified in three individuals with ataxia telangiectasia, two of whom carried a second truncating ATM mutation (Mitui M et al. Hum. Mutat. 2003 Jul;22:43-50; Carranza D et al. Neuromolecular Med. 2017 Mar;19:161-174). Of note, this alteration is also designated as 8874_8877delTGAC and 8875_8878delGACT in published literature. 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.
Color Health, Inc RCV000494628 SCV000903724 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169561 SCV001363786 pathogenic Ataxia-telangiectasia syndrome 2019-11-07 criteria provided, single submitter clinical testing Variant summary: ATM c.8876_8879delACTG (p.Asp2959GlyfsX3) 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 1.2e-05 in 251380 control chromosomes (gnomAD). c.8876_8879delACTG has been reported in the literature in homozygous and compound heterozygous individuals affected with Ataxia-Telangiectasia (Carranza_2017, Mitui_2003). These data indicate that the variant is likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrate the variant to cause absence of ATM protein expression and to confer intermediate radiosensitivity (Carranza_2017). Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=4) / likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Spanish ATM Cancer Susceptibility Variant Interpretation Working Group RCV000494628 SCV001911492 pathogenic Hereditary cancer-predisposing syndrome 2020-06-17 criteria provided, single submitter clinical testing The c.8876_8879del (p.Asp2959Glyfs*3) frameshift variant is predicted to result in a premature stop codon that leads to a truncated or absent protein, due to nonsense mediated decay (NMD) (PVS1). It has an allele frequency of 0.0013%, (3/236,852 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.0058%, (2/34,246 alleles) in the Latino / Admixed American subpopulation (no population frequency criterion met; It has been described in trans with the likely pathogenic ATM variant c.8977C>T in an ataxia-telangiectasia proband and in homozygosis in another, which awards 1.5 points to this variant as per ClinGen SVI Recommendation for in trans Criterion (PM3; PMID: 12815592, 27664052). Lymphoblastoid cell lines of the homozygous patient showed no ATM protein expression and intermediate radiosensitivity (PS3_Supporting; PMID: 27664052). Therefore, this variant meets criteria to be classified as pathogenic. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PVS1 + PM3 + PS3_Supporting (PMID: 33280026).

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