ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2192dup (p.Tyr731Ter) (rs1478081526)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780925 SCV000918580 likely pathogenic Ataxia-telangiectasia syndrome 2018-12-14 criteria provided, single submitter clinical testing Variant summary: ATM c.2192dupA (p.Tyr731X) 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 (eg. c.3049C>T (p.Gln1017X), c.3372C>G (p.Tyr1124X), c.3663G>A (p.Trp1221X)). The variant allele was found at a frequency of 4.1e-06 in 246020 control chromosomes (gnomAD). c.2192dupA has been reported in the literature in individuals affected with Ataxia-Telangiectasia and Breast Cancer (Nunziato_2019, Magliozzi_2006, Saviozzi_2003). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. However, a ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) exists for a different variant (ATM c.2193C>A) which causes the same protein alteration (p.Tyr731*) as the variant reported here; the specific variant is cited in ClinVar as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000780925 SCV000964405 pathogenic Ataxia-telangiectasia syndrome 2019-10-02 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr731*) 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 observed in an individual affected with ataxia-telangiectasia (PMID: 12655570). This variant is also known as c.2192_2193insA in the literature. ClinVar contains an entry for this variant (Variation ID: 633063). 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 RCV001014686 SCV001175426 pathogenic Hereditary cancer-predisposing syndrome 2019-08-16 criteria provided, single submitter clinical testing The c.2192dupA pathogenic mutation, located in coding exon 13 of the ATM gene, results from a duplication of A at nucleotide position 2192, causing a translational frameshift with a predicted alternate stop codon (p.Y731*). This truncating mutation (described as c.2192_2193insA) was identified in conjunction with a second mutation in a cohort of Italian patients with classic ataxia telangiectasia (A-T) (Saviozzi S et al. Hum. Mutat. 2003 Apr; 21(4):450). This alteration was identified in an Italian patient diagnosed with breast cancer, who also had first-degree relatives diagnosed with breast and brain cancers (Nunziato M et al. Anal. Chim. Acta. 2019 Jan;1046:154-162), as well as in one control and none of 3030 pancreatic cancer patients undergoing multigene panel testing for hereditary cancer risk (Hu C et al. JAMA. 2018 06;319:2401-2409). In addition to the clinical data presented in the literature, since frameshifts are typically deleterious in nature, 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.

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