The human RAD50 gene (hRAD50) is located on chromosome 5q31 and encodes the 153 kDa RAD50 protein. It plays key roles in DNA double strand breaks (DSBs) repairs, which are crucial to safeguarding genome integrity and sustaining tumor suppression. Biallelic RAD50 mutations are also associated with Nijmegen breakage syndrome-like disorder (autosomal recessive). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we only focus on autosomal dominant hereditary ovarian cancer (refute the association with ovarian cancer) in this curation. Evidence refuting this gene-disease relationship includes case-control data (0 Point) and experimental data (0 Point). This gene-disease relationship has been studied in at least 2 large case-control studies at the aggregate variant level (PMID: 28888541, 31406321). Both case-control studies did not support the association of ovarian cancer. Several case level studies were also found, in which individuals with ovarian cancer were tested by multigene panels that included RAD50. One pathogenic variant was identified in RAD50 gene out of 360 women with ovarian cancer (PMID: 22006311), while most studies did not identify pathogenic variants in the RAD50 gene (PMID: 29020732, 36531003, 31472684). A study on a mouse homozygous for a hypomorphic RAD50 allele (pLys22Met) resulted in ~20% of mice died with metastatic thymic lymphoma, splenic hyperplasia or myeloid leukemia. However, these mice did not develop ovarian cancer. (0 point, PMID: 12208847). Another study showed tumorigenesis in RAD50 mutant medaka, but it was not seen in the ovaries (PMID: 37098078). In summary, given the lack of significant association in large case-control studies and a number of ovarian cancer cohort studies not finding an association with RAD50 there is convincing evidence refuting the association between RAD50 and autosomal dominant hereditary ovarian cancer, which significantly outweighs the evidence supporting the association. This gene-disease pair was originally evaluated as disputed by the Breast/Ovarian Cancer GCEP on 10/26/2016. This re-curation was approved as refuted by the ClinGen Hereditary Cancer GCEP on 2/23/2024 (SOP Version 10).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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