ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000017.10) (NC_000017.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
21822267 Loveday et al. (2011) identified eight inactivating RAD51D mutations (four nonsense: p.Trp268X, p.Arg186X, p.Arg186X, p.Arg253X; two fs: c.363delA and c.270_271dupTA; two splicing: c.480+1G>A and c.345G>C) in unrelated individuals from 911 breast-ovarian cancer families compared with one in 1060 controls (P=0.01). To further explore the role of RAD51D mutations in breast cancer predisposition, they sequenced the gene in an additional series of 737 unrelated individuals from pedigrees in which there was familial breast cancer but no ovarian cancer. They did not identify any inactivating mutations (0/737 cases vs 1/1060 controls P=1.0). Their data clearly demonstrate that RAD51D is an ovarian cancer predisposition gene but further studies in familial and sporadic ovarian cancer series would be of value to further clarify the risks of ovarian cancer.
30165555 Chen X et al. (2018). A total of 29 cases (0.38%) carried deleterious RAD51D germline mutations among this cohort of 7657 unselected breast cancer patients. The RAD51D recurrent mutation p.K91fs was identified in 18 cases (0.24%) of these 7657 patients. In contrast, the p.K91fs mutation was found in 8 of 7947 healthy controls with a frequency of 0.10%. The RAD51D p.K91fs mutation was significantly associated with increased breast cancer risk in unselected breast cancer [odds ratio?=?2.34, 95% confidence interval (CI) 1.02-5.38; P?=?0.040].
22986143 Wickramanyake et al 2012. They sequenced RAD51D in germline DNA from 360 individuals with primary ovarian, peritoneal or fallopian tube carcinoma who were not selected for age of cancer onset or family history. Of 360 cases, three (0.8%) carried loss-of-function mutations in RAD51D. All three subjects had ovarian carcinoma; one was also diagnosed with a synchronous endometrial carcinoma. Only one of the three subjects had a family history of breast or ovarian cancer. They also sequenced RAD51D in 459 probands from 226 high risk breast cancer families who were wild type for 21 breast and ovarian cancer genes. Among the 449 women and 10 men with familial breast cancer, none carried a loss of function mutation in RAD51D. These data support the previous observation that loss-of-function mutations in RAD51D predispose to ovarian carcinoma but not to breast carcinoma.

Haploinsufficiency phenotype comments:

Through linkage analysis and association studies, germline loss of function variants in RAD51D were identified in women affected by familial ovarian cancer, with or without breast cancer. All these studies concluded that RAD51D is a moderate penetrance susceptibility gene for ovarian cancer and likely does not contribute significantly to breast cancer risk. Additional studies: PMID: 28646019: Functionally null RAD51D Missense Mutation Associates Strongly with Ovarian Carcinoma. PMID: 29409816. S?nchez-Berm?dez AI et al. 2018. In the present study, a mutation analysis was performed on non BRCA1/2 families. RAD51D genes were analyzed in 77 families. the RAD51D pathogenic variant c.694C?>?T was described in an ovarian cancer family (1.3%). No large genomic rearrangements (LGRs) were found. RAD51D carriers suffered from premenopausal ovarian tumors. PMID: 22415235. D.J. Osher et al. 2012. They identified one previously reported deleterious mutation, p.Arg186(*) (c.556C>T), and two novel variants; missense substitution p.Cys119Arg and an intronic variant c.83-26A>G. p.Arg186(*) segregated with the disease in the family and two ovarian carcinomas available for analysis. This study showed that RAD51D mutations are more likely to be found in families with two or more ovarian cancers, or in probands with first-degree relatives with ovarian cancer. PMID: 25445424 Baker JL 2015. A truncating pathogenic mutation in RAD51D (p.R186X; c. 556C>T) was identified in a 36-year-old woman with a high-grade, triple negative invasive ductal carcinoma and no evidence of ovarian cancer. A maternal aunt with medullary breast cancer diagnosed at age 54 also carried the mutation, as does the maternal half-uncle with bone and prostate cancers.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

No evidence for triplosensitivity.