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Here, we studied germline <jats:italic>ATM<\/jats:italic> variants occurring in a real\u2010world cohort of 336 patients with chronic lymphocytic leukaemia (CLL) and public cancer whole\u2010exome\/genome\u2010sequencing datasets (445 CLL, 75 mantle cell lymphoma, 216 metastatic breast cancer, 140 lung cancer patients). We found that two\u2010thirds of rare germline <jats:italic>ATM<\/jats:italic> variants are pathogenic (18%\u201350%) or VUS\u2010predicted pathogenic (50%\u201382%), depending on cancer type and reaching a prevalence of up to 8%, and one\u2010third are VUS\u2010predicted benign. Patients with both pathogenic and VUS\u2010predicted pathogenic variants, all heterozygous, mostly missense, are more predisposed to biallelic <jats:italic>ATM<\/jats:italic> inactivation by acquiring deletion (del)11q than patients without these variants, similar to patients with somatic <jats:italic>ATM<\/jats:italic> variants. A functional assay of ATM activity in primary CLL cells proved that VUS\u2010predicted pathogenic <jats:italic>ATM<\/jats:italic> variants partially reduce ATM activity and concurrent del(11q) leads to complete loss of ATM activity. The rare germline variants were associated with reduced progression\u2010free survival in CLL on novel agents, comparable to somatic <jats:italic>ATM<\/jats:italic> or <jats:italic>TP53<\/jats:italic> disruptions. Our results highlight the need to determine the pathogenicity of VUS in clinically relevant genes such as <jats:italic>ATM<\/jats:italic>.<\/jats:p>","DOI":"10.1111\/bjh.18419","type":"journal-article","created":{"date-parts":[[2022,8,27]],"date-time":"2022-08-27T05:44:26Z","timestamp":1661579066000},"page":"371-381","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Rare germline <i>ATM<\/i> variants of uncertain significance in chronic lymphocytic leukaemia and other cancers"],"prefix":"10.1111","volume":"199","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5210-4504","authenticated-orcid":false,"given":"Anna","family":"Petrackova","sequence":"first","affiliation":[{"name":"Department of Immunology, Faculty of Medicine and Dentistry Palack\u00fd University and University Hospital Olomouc  Olomouc Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3067-7867","authenticated-orcid":false,"given":"Jakub","family":"Savara","sequence":"additional","affiliation":[{"name":"Department of Immunology, Faculty of Medicine and Dentistry Palack\u00fd University and University Hospital Olomouc  Olomouc Czech Republic"},{"name":"Department of Computer Science Faculty of Electrical Engineering and Computer Science VSB\u2010Technical University of Ostrava  Ostrava Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0839-3841","authenticated-orcid":false,"given":"Peter","family":"Turcsanyi","sequence":"additional","affiliation":[{"name":"Department of Hemato\u2010Oncology Faculty of Medicine and Dentistry, Palack\u00fd University and University Hospital Olomouc  Olomouc Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Petr","family":"Gajdos","sequence":"additional","affiliation":[{"name":"Department of Computer Science Faculty of Electrical Engineering and Computer Science VSB\u2010Technical University of Ostrava  Ostrava Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomas","family":"Papajik","sequence":"additional","affiliation":[{"name":"Department of Hemato\u2010Oncology Faculty of Medicine and Dentistry, Palack\u00fd University and University Hospital Olomouc  Olomouc Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8969-4197","authenticated-orcid":false,"given":"Eva","family":"Kriegova","sequence":"additional","affiliation":[{"name":"Department of Immunology, Faculty of Medicine and Dentistry Palack\u00fd University and University Hospital Olomouc  Olomouc Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,8,26]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2017.201"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-15905-6"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2020.08.017"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.30808"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.leukres.2017.09.012"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-18-1089"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/1098-1004(200009)16:3<232::AID-HUMU6>3.0.CO;2-L"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1007355"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12881-019-0760-8"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1158\/1940-6207.CAPR-20-0448"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature14666"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2019002385"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1002201"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.129684.111"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2019.00851"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12082120"},{"key":"e_1_2_12_18_1","unstructured":"Genome Aggregation Database (gnomAD)[(accessed on 20 August 2021)]; 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