Barbora Stastna

1 BACKGROUND The Fanconi anemia (FA) genes encode at least 22 proteins that form multiprotein complexes involved in the resolution of interstrand DNA interstrand cross-links and the precise repair of DNA double-strand breaks via homologous recombination.1 While biallelic germline pathogenic variants (GPVs) in these genes cause FA (a syndrome characterized by morphologic abnormalities, bone marrow failure, and increased risk of malignancy development), monoallelic GPVs in five FA genes...

PURPOSE: Germline pathogenic variants in CHEK2 confer moderately elevated breast cancer risk (odds ratio, OR ∼ 2.5), qualifying carriers for enhanced breast cancer screening. Besides pathogenic variants, dozens of missense CHEK2 variants of uncertain significance (VUS) have been identified, hampering the clinical utility of germline genetic testing (GGT). EXPERIMENTAL DESIGN: We collected 460 CHEK2 missense VUS identified by the ENIGMA consortium in 15 countries.

1 INTRODUCTION The MRE11, RAD50, and NBN genes code for the constituents of the nuclear heterotrimeric MRN protein complex sensing DNA double-strand breaks.1 The MRN complex acts as a DNA damage sensor, aids in the selection of DNA repair strategies (facilitating homologous recombination repair) and participates in intracellular responses to DNA damage through multiple protein–protein interactions.2 Carriers of bi-allelic germline pathogenic variants (gPV) develop rare autosomal recessive...