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We examined pathogenic\/likely pathogenic (P\/LP)\n                    <jats:italic>CHEK2<\/jats:italic>\n                    variants in patients with hereditary HMs (HHMs), a solid tumor risk cohort, public datasets, and a knock-in mouse model. In the HHM cohort, 57 probands had germline P\/LP\n                    <jats:italic>CHEK2<\/jats:italic>\n                    variants, mostly p.I157T (53%, 30\/57). Among\n                    <jats:italic>CHEK2<\/jats:italic>\n                    p.I157T carriers, 43% (19\/44) had myeloid malignancies, 32% (14\/44) had lymphoid malignancies, and 2% (1\/44) had both. Among those with other germline P\/LP\n                    <jats:italic>CHEK2<\/jats:italic>\n                    alleles, 36% (13\/36) had myeloid malignancies, 28% (10\/36) had lymphoid malignancies, and 6% (2\/36) had both.\n                    <jats:italic>CHEK2<\/jats:italic>\n                    p.I157T was enriched in HM patients (OR 6.44, 95%CI 3.68\u201310.73,\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20090.001). In a solid tumor risk cohort, 36% (15\/42) of\n                    <jats:italic>CHEK2<\/jats:italic>\n                    p.I157T patients had a HM family history. A genome wide association study showed enrichment of\n                    <jats:italic>CHEK2<\/jats:italic>\n                    loss-of-function variants with myeloid leukemia (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20095.78e\n                    <jats:sup>\u22127<\/jats:sup>\n                    ). In public acute myeloid leukemia (AML) datasets, 1% (16\/1348) of patients had P\/LP\n                    <jats:italic>CHEK2<\/jats:italic>\n                    variants. In a public myelodysplastic neoplasms (MDS) dataset, 2% (5\/214) had P\/LP\n                    <jats:italic>CHEK2<\/jats:italic>\n                    variants.\n                    <jats:italic>Chek2<\/jats:italic>\n                    p.I161T mice, homologous to human p.I157T, had worse survival as heterozygotes (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.037) or homozygotes (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.005), with fewer Lin-CD34+ and Lin-cKit+ cells. Our data suggest P\/LP\n                    <jats:italic>CHEK2<\/jats:italic>\n                    variants are HHM risk alleles.\n                  <\/jats:p>","DOI":"10.1038\/s41375-025-02635-1","type":"journal-article","created":{"date-parts":[[2025,5,7]],"date-time":"2025-05-07T02:51:50Z","timestamp":1746586310000},"page":"1702-1713","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Predisposition to hematopoietic malignancies by deleterious germline CHEK2 variants"],"prefix":"10.1038","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4718-5212","authenticated-orcid":false,"given":"Ryan J.","family":"Stubbins","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Arnovitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennie","family":"Vagher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7049-1536","authenticated-orcid":false,"given":"Anase","family":"Asom","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melody","family":"Perpich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madeline","family":"Pies","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Imo J.","family":"Akpan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward","family":"Chew","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Bridgers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6753-892X","authenticated-orcid":false,"given":"Aly","family":"Karsan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Courtnee","family":"Rodgers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9956-1374","authenticated-orcid":false,"given":"Ashwin","family":"Koppayi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hatice","family":"Basdag","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael W.","family":"Drazer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soma","family":"Das","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Afaf E. 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