Rare germline ATM variants of uncertain significance in chronic lymphocytic leukaemia and other cancers
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00098892%3A_____%2F22%3A10157152" target="_blank" >RIV/00098892:_____/22:10157152 - isvavai.cz</a>
Alternative codes found
RIV/61989100:27240/22:10250456 RIV/61989592:15110/22:73614595
Result on the web
<a href="https://onlinelibrary.wiley.com/doi/10.1111/bjh.18419" target="_blank" >https://onlinelibrary.wiley.com/doi/10.1111/bjh.18419</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1111/bjh.18419" target="_blank" >10.1111/bjh.18419</a>
Alternative languages
Result language
angličtina
Original language name
Rare germline ATM variants of uncertain significance in chronic lymphocytic leukaemia and other cancers
Original language description
Germline pathogenic ATM (ataxia-telangiectasia mutated) variants are associated with the risk of multiple cancers; however, genetic testing reveals a large number of ATM variants of uncertain significance (VUS). Here, we studied germline ATM variants occurring in a real-world cohort of 336 patients with chronic lymphocytic leukaemia (CLL) and public cancer whole-exome/genome-sequencing datasets (445 CLL, 75 mantle cell lymphoma, 216 metastatic breast cancer, 140 lung cancer patients). We found that two-thirds of rare germline ATM variants are pathogenic (18%-50%) or VUS-predicted pathogenic (50%-82%), depending on cancer type and reaching a prevalence of up to 8%, and one-third are VUS-predicted benign. Patients with both pathogenic and VUS-predicted pathogenic variants, all heterozygous, mostly missense, are more predisposed to biallelic ATM inactivation by acquiring deletion (del)11q than patients without these variants, similar to patients with somatic ATM variants. A functional assay of ATM activity in primary CLL cells proved that VUS-predicted pathogenic ATM 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-free survival in CLL on novel agents, comparable to somatic ATM or TP53 disruptions. Our results highlight the need to determine the pathogenicity of VUS in clinically relevant genes such as ATM.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30205 - Hematology
Result continuities
Project
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Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2022
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
British Journal of Haematology
ISSN
0007-1048
e-ISSN
1365-2141
Volume of the periodical
199
Issue of the periodical within the volume
3
Country of publishing house
US - UNITED STATES
Number of pages
11
Pages from-to
371-381
UT code for WoS article
000846456200001
EID of the result in the Scopus database
2-s2.0-85137566715