ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4852C>T (p.Arg1618Ter) (rs762083530)

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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 RCV000166912 SCV000217730 pathogenic Hereditary cancer-predisposing syndrome 2018-06-13 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000483137 SCV000568325 pathogenic not provided 2016-11-09 criteria provided, single submitter clinical testing This variant is denoted ATM c.4852C>T at the cDNA level and p.Arg1618Ter (R1618X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in the heterozygous state in at least one case of breast cancer and in the compound heterozygous state in at least one case of ataxia-telangiectasia (Paglia 2010, Hacia 1998), and is considered pathogenic.
Invitae RCV000525721 SCV000622535 pathogenic Ataxia-telangiectasia syndrome 2019-12-28 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg1618*) in the ATM gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs762083530, ExAC 0.006%). This variant has been observed in the homozygous and compound heterozygous state in individuals affected with ataxia telangiectasia (PMID: 9872980, 15843990). This variant has also been reported in the heterozygous state in an individual affected with breast cancer (PMID: 19404735). ClinVar contains an entry for this variant (Variation ID: 187207). Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). For these reasons, this variant has been classified as Pathogenic.
Color RCV000166912 SCV000682226 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Counsyl RCV000525721 SCV000800324 pathogenic Ataxia-telangiectasia syndrome 2018-05-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000525721 SCV001361263 pathogenic Ataxia-telangiectasia syndrome 2019-08-29 criteria provided, single submitter clinical testing Variant summary: ATM c.4852C>T (p.Arg1618X) 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 4e-06 in 251340 control chromosomes (gnomAD). c.4852C>T has been reported in the literature in multiple individuals affected with Ataxia-Telangiectasia (Babaei_2005, Hacia_1998, Micol_2011) and in at least one individual affected with breast cancer (Paglia_2010). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function using a cell line derived from a patient (who carried the variant of interest and another variant) demonstrated decreased phosphorylation of ATM target proteins, defective cell cycle checkpoint control following exposure to Camptothecin (CPT) and severely decreased ATM protein expression (Fievet_2019). Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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