ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.742C>T (p.Arg248Ter) (rs730881336)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000211945 SCV000209680 pathogenic not provided 2016-03-16 criteria provided, single submitter clinical testing This variant is denoted ATM c.742C>T at the cDNA level and p.Arg248Ter (R248X) 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 ataxia-telangiectasia patients in the compound heterozygous state (Mitui 2005, Sasaki 1998), and in at least one breast cancer patient who also carried a BRCA2 nonsense variant (Churpek 2015). This variant is considered pathogenic.
Ambry Genetics RCV000159678 SCV000217771 pathogenic Hereditary cancer-predisposing syndrome 2018-04-02 criteria provided, single submitter clinical testing The p.R248* pathogenic mutation (also known as c.742C>T), located in coding exon 6 of the ATM gene, results from a C to T substitution at nucleotide position 742. This changes the amino acid from an arginine to a stop codon within coding exon 6. This mutation was identified in the compound heterozygous state in three individuals with ataxia telangiectasia, although phase was not confirmed (Sasaki T et al. Hum. Mutat. 1998;12:186-95; Mitui M et al. Ann. Hum. Genet. 2005 Nov;69:657-64). This alteration was also reported in 1/10,030 individuals undergoing hereditary cancer panel testing through a clinical laboratory (Susswein LR et al. Genet. Med. 2016 Aug;18:823-32) and in one individual from a cohort of 692 men with metastatic prostate cancer (Pritchard CC et al. N. Engl. J. Med. 2016 Aug;375:443-53). 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.
Counsyl RCV000410046 SCV000485320 likely pathogenic Ataxia-telangiectasia syndrome 2015-11-20 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515228 SCV000611167 pathogenic Familial cancer of breast; Ataxia-telangiectasia syndrome 2017-05-18 criteria provided, single submitter clinical testing
Invitae RCV000410046 SCV000622747 pathogenic Ataxia-telangiectasia syndrome 2020-10-01 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg248*) in the ATM gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs730881336, ExAC 0.01%). This variant has been reported in individuals affected with ataxia telangiectasia (PMID: 9711876, 16266405), prostate cancer (PMID: 27433846) and breast cancer (PMID: 26681312, 28281021). ClinVar contains an entry for this variant (Variation ID: 181913). Loss-of-function variants in ATM are known to be pathogenic (PMID: 25614872, 23807571). For these reasons, this variant has been classified as Pathogenic.
Color Health, Inc RCV000159678 SCV000687770 pathogenic Hereditary cancer-predisposing syndrome 2021-02-16 criteria provided, single submitter clinical testing This variant changes 1 nucleotide in exon 7 of the ATM gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in the compound heterozygous state in individuals affected with ataxia telangiectasia (PMID: 9711876, 16266405, 30402232). This variant has also been reported in individuals affected with breast cancer (PMID: 26681312, 28281021) or prostate cancer (PMID: 27433846). This variant has been identified in 2/245760 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000709708 SCV000839882 pathogenic Familial cancer of breast 2017-05-24 criteria provided, single submitter clinical testing This c.742C>T (p.Arg248*) variant in the ATM gene has previously been reported in two Japanese patients with ataxia telangiectasia [PMID 9711876]. Both patients were compound heterozygous for this variant and a loss of function variant [PMID 9711876]. This c.742C>T encodes for a premature stop codon in exon 7 at amino acid position 248 of the ATM protein, leading to a loss of function of the protein. This variant has been observed in one heterozygous East Asian individual in the ExAC database (http://exac.broadinstitute.org/variant/11-108115594-C-T). It is thus classified as a pathogenic variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000410046 SCV001363667 pathogenic Ataxia-telangiectasia syndrome 2020-12-26 criteria provided, single submitter clinical testing Variant summary: ATM c.742C>T (p.Arg248X) 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. The variant allele was found at a frequency of 8e-06 in 251010 control chromosomes. c.742C>T has been reported in the literature in individuals affected with Ataxia-Telangiectasia (Micol_2011, Sasaki_1998, Mitui_2005, Ye_2018), Breast Cancer (Susswein_2015), and Prostate Cancer (Pritchard_2016). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven 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 (n=6)/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Department of Rehabilitation Medicine, Incheon St. Mary’s Hospital,College of Medicine, The Catholic University of Korea RCV000410046 SCV000999057 pathogenic Ataxia-telangiectasia syndrome 2019-11-20 no assertion criteria provided clinical testing The patient has another variant on the other allele (arr[GRCh37] 11q22.3(108151766-108183226)x1, 31460 bp).

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