RAD50

Inheritance Pattern: AR

Disease ID:MONDO:0013118

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0016248

Submitter: ClinGen

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).

Inheritance Pattern: AD

Disease ID:MONDO:0016419

Submitter: ClinGen

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. RAD50 null mutations cause embryonic lethality in mice, while hypomorphic RAD50 mutant (RAD50S/S) mice exhibit growth defects and cancer predisposition. Human RAD50-mutated cells exhibit a phenotype that includes sensitivity to ionizing radiation, a deficit in DNA DSB repair, and chromosomal instability. Therefore, mutations in the RAD50 gene that impair RAD50 function may contribute to the development and progression of cancers. Biallelic RAD50 mutations are associated with Nijmegen breakage syndrome-like disorder. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we only focus on hereditary breast cancer (refute the association with breast cancer) in this curation. Evidence refuting this gene-disease relationship includes case-control data, while experimental data supports the role of RAD50 in DNA repair. **Summary of Case-Control Data: 1 POINTS** This gene-disease relationship has been studied in at least 8 case-control studies at the aggregate variant level. In 2021, two large case-control studies [CARRIERS (PMID: 33471974) and BCAC (PMID: 33471991); both with more than 32 thousand cases and controls] did not identify a significant association of aggregate loss of function (LOF) variants in RAD50 and breast cancer. Another large case-control study with more than 26 thousand cases and controls (PMID: 28418444) also did not show an association. Smaller case-control studies in China (PMID: 29726012 and 34606182), France (PMID: 30303537) and Australia (PMID: 34117267) produced similar results. Only one case-control study from Finland (PMID: 16474176) showed an association for RAD50 variants with breast cancer. The study population was small and received only 1 point. **Summary of Experimental Data: 1.75 POINTS** While case control studies did not support the gene-disease association, there is experimental evidence showing the association of RAD50 with BRCA1 in DNA repair (0.5 point, PMID: 10426999), and irregular expression of RAD50 in irradiated skin of radiosensitive cancer patients (0.25 point, PMID: 15150571). A study on RAD50 687delT showed decreased expression in lymphoblastoid cell lines but normal subcellular localization of the protein in 3 breast cancer tumors from mutation carriers (1 point, PMID: 16385572). Lastly, 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 mammary cancer. (0 point, PMID: 12208847). **Overall Summary:** In summary, given the lack of significant association in large breast cancer case-control studies to date, there is convincing evidence refuting the association between RAD50 and autosomal dominant hereditary breast cancer, which significantly outweighs the evidence supporting the association. This gene-disease pair was originally evaluated as limited by the Breast/Ovarian Cancer GCEP on 12/14/2016. This re-curation was approved by the ClinGen Hereditary Diseases GCEP on 2/17/2023 (SOP Version 9).

Inheritance Pattern: AR

Disease ID:MONDO:0013118

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0013118

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0013118

Submitter: PanelApp Australia