{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T14:04:11Z","timestamp":1793714651604,"version":"4.6.1"},"reference-count":64,"publisher":"American Medical Association (AMA)","issue":"11","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Oncol"],"published-print":{"date-parts":[[2022,11,1]]},"abstract":"<jats:sec id=\"ab-coi220046-4\">\n                    <jats:title>Importance<\/jats:title>\n                    <jats:p>\n                      Germline\n                      <jats:italic>CHEK2<\/jats:italic>\n                      pathogenic variants (PVs) are frequently detected by multigene cancer panel testing (MGPT), but our understanding of PVs beyond c.1100del has been limited.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"ab-coi220046-5\">\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      To compare cancer phenotypes of frequent\n                      <jats:italic>CHEK2<\/jats:italic>\n                      PVs individually and collectively by variant type.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"ab-coi220046-6\">\n                    <jats:title>Design, Setting, and Participants<\/jats:title>\n                    <jats:p>\n                      This retrospective cohort study was carried out in a single diagnostic testing laboratory from 2012 to 2019. Overall, 3783 participants with\n                      <jats:italic>CHEK2<\/jats:italic>\n                      PVs identified via MGPT were included. Medical histories of cancer in participants with frequent PVs, negative MGPT (wild type), loss-of-function (LOF), and missense were compared.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"ab-coi220046-7\">\n                    <jats:title>Main Outcomes and Measures<\/jats:title>\n                    <jats:p>\n                      Participants were stratified by\n                      <jats:italic>CHEK2<\/jats:italic>\n                      PV type. Descriptive statistics were summarized including median (IQR) for continuous variables and proportions for categorical characteristics. Differences in age and proportions were assessed with Wilcoxon rank sum and Fisher exact tests, respectively. Frequencies, odds ratios (ORs), 95% confidence intervals were calculated, and\n                      <jats:italic>P<\/jats:italic>\n                      values were corrected for multiple comparisons where appropriate.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"ab-coi220046-8\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Of the 3783 participants with\n                      <jats:italic>CHEK2<\/jats:italic>\n                      PVs, 3473 (92%) were female and most reported White race. Breast cancer was less frequent in participants with p.I157T (OR, 0.66; 95% CI, 0.56-0.78;\n                      <jats:italic>P<\/jats:italic>\n                      &amp;amp;lt;.001), p.S428F (OR, 0.59; 95% CI. 0.46-0.76;\n                      <jats:italic>P<\/jats:italic>\n                      &amp;amp;lt;.001), and p.T476M (OR, 0.74; 95% CI, 0.56-0.98;\n                      <jats:italic>P\u2009<\/jats:italic>\n                      =\u2009.04) PVs compared with other PVs and an association with nonbreast cancers was not found. Following the exclusion of p.I157T, p.S428F, and p.T476M, participants with monoallelic\n                      <jats:italic>CHEK2<\/jats:italic>\n                      PV had a younger age at first cancer diagnosis (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&amp;amp;lt;\u2009.001) and were more likely to have breast (OR, 1.83; 95% CI, 1.66-2.02;\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&amp;amp;lt;\u2009.001), thyroid (OR, 1.63; 95% CI, 1.26-2.08;\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&amp;amp;lt;\u2009.001), and kidney cancer (OR, 2.57; 95% CI, 1.75-3.68;\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&amp;amp;lt;\u2009.001) than the wild-type cohort. Participants with a\n                      <jats:italic>CHEK2<\/jats:italic>\n                      PV were less likely to have a diagnosis of colorectal cancer (OR, 0.62; 95% CI, 0.51-0.76;\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&amp;amp;lt;\u2009.001) compared with those in the wild-type cohort. There were no significant differences between frequent\n                      <jats:italic>CHEK2<\/jats:italic>\n                      PVs and c.1100del and no differences between\n                      <jats:italic>CHEK2<\/jats:italic>\n                      missense and LOF PVs.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"ab-coi220046-9\">\n                    <jats:title>Conclusions and Relevance<\/jats:title>\n                    <jats:p>\n                      <jats:italic>CHEK2<\/jats:italic>\n                      PVs, with few exceptions (p.I157T, p.S428F, and p.T476M), were associated with similar cancer phenotypes irrespective of variant type.\n                      <jats:italic>CHEK2<\/jats:italic>\n                      PVs were not associated with colorectal cancer, but were associated with breast, kidney, and thyroid cancers. Compared with other\n                      <jats:italic>CHEK2<\/jats:italic>\n                      PVs, the frequent p.I157T, p.S428F, and p.T476M alleles have an attenuated association with breast cancer and were not associated with nonbreast cancers. These data may inform the genetic counseling and care of individuals with\n                      <jats:italic>CHEK2<\/jats:italic>\n                      PVs.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1001\/jamaoncol.2022.4071","type":"journal-article","created":{"date-parts":[[2022,9,22]],"date-time":"2022-09-22T12:19:45Z","timestamp":1663849185000},"page":"1598","source":"Crossref","is-referenced-by-count":94,"title":["Differences in Cancer Phenotypes Among Frequent\n                    <i>CHEK2<\/i>\n                    Variants and Implications for Clinical Care\u2014Checking\n                    <i>CHEK2<\/i>"],"prefix":"10.1001","volume":"8","author":[{"given":"Brittany L.","family":"Bychkovsky","sequence":"first","affiliation":[{"name":"Division of Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Boston, Massachusetts"},{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts"},{"name":"Harvard 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