Leiden University Scholarly Publications

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Boonen, R.A.C.M. (2023)

Functional analysis of genetic variants in PALB2 and CHEK2: linking functional impact with cancer risk

Doctoral Thesis
Pathogenic variants in PALB2 and CHEK2 are associated with an increased risk of breast cancer. By contrast, for missense variants of uncertain significance (VUS) in these genes, the associated breast cancer risk is often unclear. To aid in their clinical classification, functional assays that determine the impact of missense VUS on PALB2 and CHK2 protein function have been performed in this thesis. By means of these functional analyses, numerous missense VUS (in both PALB2 and CHEK2) have been identified that are, from a functional viewpoint, just as damaging as known pathogenic (i.e., truncating) variants. In agreement, we observe that the level of impaired protein function correlates with the degree of increased breast cancer risk. Overall, these findings suggest that damaging PALB2 and CHEK2 missense VUS are associated with a risk of breast cancer similar to that of protein-truncating variants in these genes. This indicates the urgency of expanding the functional...Show morePathogenic variants in PALB2 and CHEK2 are associated with an increased risk of breast cancer. By contrast, for missense variants of uncertain significance (VUS) in these genes, the associated breast cancer risk is often unclear. To aid in their clinical classification, functional assays that determine the impact of missense VUS on PALB2 and CHK2 protein function have been performed in this thesis. By means of these functional analyses, numerous missense VUS (in both PALB2 and CHEK2) have been identified that are, from a functional viewpoint, just as damaging as known pathogenic (i.e., truncating) variants. In agreement, we observe that the level of impaired protein function correlates with the degree of increased breast cancer risk. Overall, these findings suggest that damaging PALB2 and CHEK2 missense VUS are associated with a risk of breast cancer similar to that of protein-truncating variants in these genes. This indicates the urgency of expanding the functional characterization of missense VUS in both PALB2 and CHEK2 to further understand the associated cancer risk.
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Functional analyses
Breast cancer
CHEK2
PALB2
Variant of Uncertain Significance (VUS)
Homologous recombination
DNA repair
All authors
Boonen, R.A.C.M.
Supervisor
Attikum, H. van; Devilee, P.
Co-supervisor
Vreeswijk, M.P.G.
Committee
Schmidt, M.K.; Jonkers, J.M.M.; Riele, H.P.J. te; Knipscheer, P.M.
Qualification
Doctor (dr.)
Awarding Institution
Faculty of Medicine, Leiden University Medical Center (LUMC), Leiden University
Date
2023-04-04
ISBN (print)
9789464830064

Funding

Sponsorship
KWF; European Union