{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T12:42:35Z","timestamp":1790426555574,"version":"4.1.0"},"reference-count":47,"publisher":"National Academy of Sciences","issue":"2","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2002,1,22]]},"abstract":"<jats:p>\n                    The human genetic disorder ataxia-telangiectasia (A-T) is characterized by hypersensitivity to ionizing radiation and an elevated risk of malignancy. Epidemiological data support an increased risk for breast and other cancers in A-T heterozygotes. However, screening breast cancer cases for truncating mutations in the\n                    <jats:italic>ATM<\/jats:italic>\n                    (A-T mutated) gene has failed largely to reveal an increased incidence in these patients. It has been hypothesized that ATM missense mutations are implicated in breast cancer, and there is some evidence to support this. The presence of a large variety of rare missense variants in addition to common polymorphisms in ATM makes it difficult to establish such a relationship by association studies. To investigate the functional significance of these changes we have introduced missense substitutions, identified in either A-T or breast cancer patients, into ATM cDNA before establishing stable cell lines to determine their effect on ATM function. Pathogenic missense mutations and neutral missense variants were distinguished initially by their capacity to correct the radiosensitive phenotype in A-T cells. Furthermore missense mutations abolished the radiation-induced kinase activity of ATM in normal control cells, caused chromosome instability, and reduced cell viability in irradiated control cells, whereas neutral variants failed to do so. Mutant ATM was expressed at the same level as endogenous protein, and interference with normal ATM function seemed to be by multimerization. This approach represents a means of identifying genuine ATM mutations and addressing the significance of missense changes in the\n                    <jats:italic>ATM<\/jats:italic>\n                    gene in a variety of cancers including breast cancer.\n                  <\/jats:p>","DOI":"10.1073\/pnas.012329699","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:36:44Z","timestamp":1027679804000},"page":"925-930","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":117,"title":["Missense mutations but not allelic variants alter the function of ATM by dominant interference in patients with breast cancer"],"prefix":"10.1073","volume":"99","author":[{"given":"Shaun P.","family":"Scott","sequence":"first","affiliation":[{"name":"Queensland Institute of Medical Research, PO Royal Brisbane Hospital, Herston, Brisbane 4029, Australia; Department of Radiation Oncology and Department of Biochemistry and Tumour Biology, Medical School of Hannover, OE 6410 Hannover, Germany; Cancer Care Centre, St. George Hospital, Kogarah, Sydney 2217, Australia; and Department of Surgery, University of Queensland, Herston, Brisbane 4029, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Regina","family":"Bendix","sequence":"additional","affiliation":[{"name":"Queensland Institute of Medical Research, PO Royal Brisbane Hospital, Herston, Brisbane 4029, Australia; Department of Radiation Oncology and Department of Biochemistry and Tumour Biology, Medical School of Hannover, OE 6410 Hannover, Germany; Cancer Care Centre, St. George Hospital, Kogarah, Sydney 2217, Australia; and Department of Surgery, University of Queensland, Herston, Brisbane 4029, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip","family":"Chen","sequence":"additional","affiliation":[{"name":"Queensland Institute of Medical Research, PO Royal Brisbane Hospital, Herston, Brisbane 4029, Australia; Department of Radiation Oncology and Department of Biochemistry and Tumour Biology, Medical School of Hannover, OE 6410 Hannover, Germany; Cancer Care Centre, St. George Hospital, Kogarah, Sydney 2217, Australia; and Department of Surgery, University of Queensland, Herston, Brisbane 4029, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond","family":"Clark","sequence":"additional","affiliation":[{"name":"Queensland Institute of Medical Research, PO Royal Brisbane Hospital, Herston, Brisbane 4029, Australia; Department of Radiation Oncology and Department of Biochemistry and Tumour Biology, Medical School of Hannover, OE 6410 Hannover, Germany; Cancer Care Centre, St. George Hospital, Kogarah, Sydney 2217, Australia; and Department of Surgery, University of Queensland, Herston, Brisbane 4029, 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