A decade of RAD51C/D: Germline pathogenic variants and their phenotypic
landscape
Abstract
Defects in DNA repair genes have been extensively associated to cancer
susceptibility. Germline pathogenic variants (GPV) in genes involved in
homologous recombination repair pathway predispose to cancers arising
mainly in breast and ovary, but also other tissues. The RAD51 paralogs
RAD51C and RAD51D were included in this group 10 years ago, when
germline variants were associated to non-BRCA1/2 familial ovarian
cancer. However, whether GPVs in these genes are associated with other
cancers remains unknown. Here, we have reviewed the landscape of RAD51C
and RAD51D germline variants in cancer reported in the literature during
the last decade, curating a total of 341 variants and the phenotypes
found in families with RAD51C/D variant carriers. A comprehensive
catalogue has been generated pinpointing to the existence of recurrent
variants in both genes. Investigation of pedigrees found fourteen other
cancer types reported more than five times in families with carriers of
RAD51C/D pathogenic variants. Among those, colorectal (3.72% and
4.43%) (RAD51C/D respectively), pancreatic (1.19% and 0.86%), lung
(1.27% and 2.58%), prostate (1.56% and 1.48%), and leukemia (1.56%
and 1.11%) cancer were the most prevalent types. This work highlights
how both genes might confer susceptibility to a broader spectrum of
cancer types than ovary and breast.