ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7327C>T (p.Arg2443Ter) (rs121434220)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000003175 SCV000220525 likely pathogenic Ataxia-telangiectasia syndrome 2014-07-19 criteria provided, single submitter literature only
Invitae RCV000003175 SCV000260860 pathogenic Ataxia-telangiectasia syndrome 2020-10-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg2443*) 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 individuals affected with ataxia-telangiectasia (PMID: 8808599, 10817650, 9887333, 21833744, 14586414), and individuals with prostate, breast, and pancreatic cancer (PMID: 24556621, 26822949, 26483394). ClinVar contains an entry for this variant (Variation ID: 3036). Experimental studies in heterozygous cell lines have shown that this nonsense change causes reduced ATM protein and mRNA expression, and increased sensitivity to radiation (PMID: 15101044, 14970866). 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 RCV000220229 SCV000273030 pathogenic Hereditary cancer-predisposing syndrome 2019-03-29 criteria provided, single submitter clinical testing The p.R2443* pathogenic mutation (also known as c.7327C>T), located in coding exon 49 of the ATM gene, results from a C to T substitution at nucleotide position 7327. This changes the amino acid from an arginine to a stop codon within coding exon 49. This mutation has been reported in numerous individuals with ataxia-telangiectasia (AT) (Wright J et al. Am. J. Hum. Genet. 1996 Oct;59:839-46; Guti&eacute;rrez-Enr&iacute;quez S et al. Genes Chromosomes Cancer 2004 Jun;40:109-19; Sandoval N et al. Hum. Mol. Genet. 1999 Jan;8:69-79; Li A et al. Am. J. Med. Genet. 2000 May;92:170-7; Tariq H et al. J Clin Neurol<span style="color:rgb(54, 43, 54); font-family:arial; font-size:12px"> 2018 Oct;14(4):498-504). This mutation has also been reported in a prostate cancer kindred in which it segregated with disease in an affected brother (Leongamornlert D et al. Br. J. Cancer 2014 Mar;110:1663-72) , in 2/325 high-risk Czech breast cancer patients (Lhota F et al. Clin. Genet. 2016 Oct;90:324-33), and 1/96 individuals with a personal and family history of pancreatic cancer (Hu C. et al. Cancer Epidemiol. Biomarkers Prev.<span style="color:rgb(54, 43, 54); font-family:arial; font-size:12px"> 2016 Jan;25(1):207-11). 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.
GeneDx RCV000484232 SCV000566496 pathogenic not provided 2018-11-06 criteria provided, single submitter clinical testing This pathogenic variant is denoted ATM c.7327C>T at the cDNA level and p.Arg2443Ter (R2443X) 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 homozygous and compound heterozygous states in multiple individuals with ataxia-telangiectasia (Sandoval 1999, Bernstein 2003, Anheim 2010, Tariq 2018) and in the heterozygous state in individuals with breast, pancreatic, and/or prostate cancer (Leongamornlert 2014, Hu 2016, Lhota 2016). We consider this variant to be pathogenic.
Color Health, Inc RCV000220229 SCV000687767 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000003175 SCV000694350 pathogenic Ataxia-telangiectasia syndrome 2017-02-02 criteria provided, single submitter clinical testing Variant summary: The ATM c.7327C>T (p.Arg2443X) variant results in a premature termination codon, predicted to cause absent ATM protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This prediction has been confirmed by one study showing that the ATM protein is absent in cells from a patient who carries the variant of interest and a frameshift variant (Prodosmo_2013). Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.c.7517_7520delGAGA, c.8264_8268delATAAG). One in silico tool predicts a damaging outcome for this variant. This variant has been reported in multiple AT patients and is absent in 119996 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as pathogenic.
PreventionGenetics,PreventionGenetics RCV000484232 SCV000805612 pathogenic not provided 2017-07-14 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000484232 SCV001246116 pathogenic not provided 2020-12-01 criteria provided, single submitter clinical testing
Division of Medical Genetics, University of Washington RCV001250440 SCV001424815 pathogenic Familial cancer of breast 2019-04-15 criteria provided, single submitter clinical testing The c.7327C>T variant creates a premature stop codon which is expected to lead to protein truncation or nonsense-mediated mRNA decay. Loss-of-function variants in ATM are considered pathogenic (Podralska 2014, Huang 2013). Women who are heterozygous for pathogenic variants in ATM have an increased risk for breast cancer. Men and women who are heterozygous for pathogenic variants in ATM may have an increased risk for pancreatic cancer. There are multiple reported individuals with breast, pancreatic and/or prostate cancer who are heterozygous for the c.7327C>T ATM variant (Leongamornlert 2014, Lhota 2016, Hu 2016). Individuals who are homozygous or compound heterozygous for pathogenic variants in ATM have Ataxia-telangiectasia. The c.7327C>T ATM variant has been reported in multiple individuals with Ataxia-telangiectasia who are compound heterozygous for a second ATM pathogenic variant (Soukupova 2011, Delia 2003, Li 2000, Sandoval 1999, Wright 1996). Thus, this variant is interpreted as pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000484232 SCV001447181 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Department of Molecular Diagnostics, Institute of Oncology Ljubljana RCV001250440 SCV001499653 pathogenic Familial cancer of breast 2020-04-02 criteria provided, single submitter clinical testing
OMIM RCV000003175 SCV000023333 pathogenic Ataxia-telangiectasia syndrome 1999-01-01 no assertion criteria provided literature only
CZECANCA consortium RCV001270953 SCV001451757 pathogenic Breast and/or ovarian cancer 2019-06-11 no assertion criteria provided clinical testing
CZECANCA consortium RCV001391206 SCV001593149 pathogenic Carcinoma of pancreas 2021-03-04 no assertion criteria provided case-control

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