ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function 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.

Evidence for Triplosenstive Phenotype

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.