ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6100C>T (p.Arg2034Ter) (rs532480170)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235108 SCV000149131 pathogenic not provided 2019-07-26 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 26270727, 8659541, 12552559, 11505391, 28724667, 30612635, 25525159, 14695186, 15390180, 10330348, 21833744, 0, 27913932, 26681312, 26845104, 29731985, 29478780, 29555771, 28767289, 30322717, 30607632, 31980526, 31948886)
Invitae RCV000122867 SCV000166125 pathogenic Ataxia-telangiectasia syndrome 2020-10-09 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg2034*) 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 the literature in individuals affected with ataxia-telangiectasia, breast cancer and multiple cancer types (PMID: 8659541, 21833744, 11505391, 26845104, 26681312). ClinVar contains an entry for this variant (Variation ID: 127417). 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 RCV000115222 SCV000214025 pathogenic Hereditary cancer-predisposing syndrome 2019-12-02 criteria provided, single submitter clinical testing The p.R2034* pathogenic mutation (also known as c.6100C>T), located in coding exon 41 of the ATM gene, results from a C to T substitution at nucleotide position 6100. This changes the amino acid from an arginine to a stop codon within coding exon 41. This alteration has been reported in multiple individuals with ataxia telangiectasia (Telatar M et al. Am. J. Hum. Genet. 1996 Jul;59(1):40-4; Soukupova J et al. Neuromolecular Med. 2011 Sep;13(3):204-11). It was also described breast and colon cancer cohorts (Angele S et al. Hum. Mutat. 2003 Feb;21(2):169-70; AlDubayan SH et al. Am. J. Hum. Genet. 2018 03;102(3):401-414). 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.
University of Washington Department of Laboratory Medicine, University of Washington RCV000115222 SCV000266019 likely pathogenic Hereditary cancer-predisposing syndrome 2015-11-20 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115222 SCV000292138 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Baylor Genetics RCV000122867 SCV000807216 pathogenic Ataxia-telangiectasia syndrome 2017-09-01 criteria provided, single submitter clinical testing This mutation has been previously reported as disease-causing and was found once in our laboratory in trans with a missense mutation in a 10-year-old male with global delays, myopathy, epilepsy, generalize muscle weakness, and abnormal brain MRI.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000122867 SCV001442640 pathogenic Ataxia-telangiectasia syndrome 2020-10-19 criteria provided, single submitter clinical testing Variant summary: ATM c.6100C>T (p.Arg2034X) 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 251344 control chromosomes (gnomAD). c.6100C>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Ataxia-Telangiectasia (e.g. Telatar_1996, Buzin_2003, Soukupova_2011, An_2016) and was also reported in heterozygous state in patients affected by various tumor phenotypes (e.g. Shindo_2017, Yang_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000235108 SCV001446661 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Natera, Inc. RCV000122867 SCV001457404 pathogenic Ataxia-telangiectasia syndrome 2020-09-16 no assertion criteria provided clinical testing

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