RAD51D gene’s protein product is known to be involved in the DNA repair mechanism by homologous recombination. RAD51D germline mutations have been recently associated with ovarian and breast cancer (OC and BC, respectively) predisposition. Our aim was to evaluate the frequency of hereditary RAD51D mutations in Greek patients. To address this, we have screened for RAD51D germline mutations 609 BRCA1- and BRCA2-negative patients diagnosed with OC, unselected for age or family history, and 569 BC patients diagnosed under 55 years and with an additional relative with BC or OC. We identified four pathogenic mutations in four unrelated individuals with family history of BC and/or OC. Three of the RAD51D carriers had developed BC, while the other one was an OC patient, thus accounting for a mutation frequency of 0.16% in the OC cohort and 0.53% in the BC cohort. One of the detected mutations is novel (c.738 + 1G > A), whereas the rest had been detected previously (p.Gln151Ter, p.Arg186Ter, and p.Arg300Ter). It is noteworthy that the 4 carrier families had 13 BC cases and only 4 OC cases. Our data support that RAD51D should be implemented into the comprehensive multigene panel, as mutation carriers may benefit from the administration of PARP inhibitors.
This is a preview of subscription content
Subscribe to Journal
Get full journal access for 1 year
only $9.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.
Wickramanayake A, Bernier G, Pennil C, Casadei S, Agnew KJ, Stray SM, et al. Loss of function germline mutations in RAD51D in women with ovarian carcinoma. Gynecol Oncol. 2012;127:552–5.
Ramus SJ, Harrington PA, Pye C, DiCioccio RA, Cox MJ, Garlinghouse-Jones K, et al. Contribution of BRCA1 and BRCA2 mutations to inherited ovarian cancer. Hum Mutat. 2007;28:1207–15.
Antoniou AC, Gayther SA, Stratton JF, Ponder BA, Easton DF. Risk models for familial ovarian and breast cancer. Genet Epidemiol. 2000;18:173–90.
Walsh T, Casadei S, Lee MK, Pennil CC, Nord AS, Thornton AM, et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci USA. 2011;108:18032–7.
Castera L, Krieger S, Rousselin A, Legros A, Baumann JJ, Bruet O, et al. Next-generation sequencing for the diagnosis of hereditary breast and ovarian cancer using genomic capture targeting multiple candidate genes. Eur J Hum Genet. 2014;22:1305–13.
Masson JY, Tarsounas MC, Stasiak AZ, Stasiak A, Shah R, McIlwraith MJ, et al. Identification and purification of two distinct complexes containing the five RAD51 paralogs. Genes Dev. 2001;15:3296–307.
Takata M, Sasaki MS, Tachiiri S, Fukushima T, Sonoda E, Schild D, et al. Chromosome instability and defective recombinational repair in knockout mutants of the five Rad51 paralogs. Mol Cell Biol. 2001;21:2858–66.
Loveday C, Turnbull C, Ramsay E, Hughes D, Ruark E, Frankum JR, et al. Germline mutations in RAD51D confer susceptibility to ovarian cancer. Nat Genet. 2011;43:879–82.
Osher DJ, De Leeneer K, Michils G, Hamel N, Tomiak E, Poppe B, et al. Mutation analysis of RAD51D in non-BRCA1/2 ovarian and breast cancer families. Br J Cancer. 2012;106:1460–3.
Thompson ER, Rowley SM, Sawyer S, kConfab, Eccles DM, Trainer AH, et al. Analysis of RAD51D in ovarian cancer patients and families with a history of ovarian or breast cancer. PLoS ONE. 2013;8:e54772.
Norquist BM, Harrell MI, Brady MF, Walsh T, Lee MK, Gulsuner S, et al. Inherited mutations in women with ovarian carcinoma. JAMA Oncol. 2016;2:482–90.
Couch FJ, Hart SN, Sharma P, Toland AE, Wang X, Miron P, et al. Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. J Clin Oncol. 2015;33:304–11.
Buys SS, Sandbach JF, Gammon A, Patel G, Kidd J, Brown KL, et al. A study of over 35,000 women with breast cancer tested with a 25-gene panel of hereditary cancer genes. Cancer. 2017;123:1721–30.
Couch FJ, Shimelis H, Hu C, Hart SN, Polley EC, Na J, et al. Associations between cancer predisposition testing panel genes and breast cancer. JAMA Oncol. 2017;3:1190–6.
Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988;16:1215.
den Dunnen JT, Dalgleish R, Maglott DR, Hart RK, Greenblatt MS, McGowan-Jordan J, et al. HGVS recommendations for the description of sequence variants: 2016 update. Hum Mutat. 2016;37:564–9.
Tavtigian SV, Deffenbaugh AM, Yin L, Judkins T, Scholl T, Samollow PB, et al. Comprehensive statistical study of 452 BRCA1 missense substitutions with classification of eight recurrent substitutions as neutral. J Med Genet. 2006;43:295–305.
Mathe E, Olivier M, Kato S, Ishioka C, Hainaut P, Tavtigian SV. Computational approaches for predicting the biological effect of p53 missense mutations: a comparison of three sequence analysis based methods. Nucleic Acids Res. 2006;34:1317–25.
Schwarz JM, Cooper DN, Schuelke M, Seelow D. MutationTaster2: mutation prediction for the deep-sequencing age. Nat Methods. 2014;11:361–2.
Pollard KS, Hubisz MJ, Rosenbloom KR, Siepel A. Detection of nonneutral substitution rates on mammalian phylogenies. Genome Res. 2010;20:110–21.
ExAC Browser (Beta). Exome Aggregation Consortium. http://exac.broadinstitute.org. Accessed 23 February 2018.
Desmet FO, Hamroun D, Lalande M, Collod-Béroud G, Claustres M, Béroud C. Human splicing finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res. 2009;37:e67.
Smith PJ, Zhang C, Wang J, Chew SL, Zhang MQ, Krainer AR. An increased specificity score matrix for the prediction of SF2/ASF-specific exonic splicing enhancers. Hum Mol Genet. 2006;15:2490–508.
Yeo G, Burge CB. Maximum entropy modeling of short sequence motifs with applications to RNA splicing signals. J Comput Biol. 2004;11:377–94.
Hebsgaard SM, Korning PG, Tolstrup N, Engelbrecht J, Rouzé P, Brunak S. Splice site prediction in Arabidopsis thaliana pre-mRNA by combining local and global sequence information. Nucleic Acids Res. 1996;24:3439–52.
Dogan RI, Getoor L, Wilbur WJ, Mount SM. SplicePort–an interactive splice-site analysis tool. Nucleic Acids Res. 2007;35:W285–91.
Tomancak P, Berman BP, Beaton A, Weiszmann R, Kwan E, Hartenstein V, et al. Global analysis of patterns of gene expression during Drosophila embryogenesis. Genome Biol. 2007;8:R145.
Biasini M, Bienert S, Waterhouse A, Arnold K, Studer G, Schmidt T, et al. SWISS-MODEL: modelling protein tertiary and quaternary structure using evolutionary information. Nucleic Acids Res. 2014;42:W252–8.
Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536:285–91.
Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, et al. Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Genet Med. 2017;19:1105–17.
Amendola LM, Jarvik GP, Leo MC, McLaughlin HM, Akkari Y, Amaral MD, et al. Performance of ACMG-AMP variant-interpretation guidelines among nine laboratories in the clinical sequencing Exploratory research consortium. Am J Hum Genet. 2016;98:1067–76.
Song H, Dicks E, Ramus SJ, Tyrer JP, Intermaggio MP, Hayward J, et al. Contribution of germline mutations in the RAD51B, RAD51C, and RAD51D genes to ovarian cancer in the population. J Clin Oncol. 2015;33:2901–7.
Conway AB, Lynch TW, Zhang Y, Fortin GS, Fung CW, Symington LS, et al. Crystal structure of a Rad51 filament. Nat Struct Mol Biol. 2004;11:791–6.
Walsh T, King MC. Ten genes for inherited breast cancer. Cancer Cell. 2007;11:103–5.
Bowtell DD. The genesis and evolution of high-grade serous ovarian cancer. Nat Rev Cancer. 2010;10:803–8.
Baker JL, Schwab RB, Wallace AM, Madlensky L. Breast cancer in a RAD51D mutation carrier: case report and review of the literature. Clin Breast Cancer. 2015;15:e71–5.
Lilyquist J, LaDuca H, Polley E, Davis BT, Shimelis H, Hu C, et al. Frequency of mutations in a large series of clinically ascertained ovarian cancer cases tested on multi-gene panels compared to reference controls. Gynecol Oncol. 2017;147:375–80.
Harter P, Hauke J, Heitz F, Reuss A, Kommoss S, Marmé F, et al. Prevalence of deleterious germline variants in risk genes including BRCA1/2 in consecutive ovarian cancer patients (AGO-TR-1). PLoS ONE. 2017;12:e0186043.
Pelttari LM, Kiiski J, Nurminen R, Kallioniemi A, Schleutker J, Gylfe A, et al. A Finnish founder mutation in RAD51D: analysis in breast, ovarian, prostate, and colorectal cancer. J Med Genet. 2012;49:429–32.
Gutierrez-Enriquez S, Bonache S, de Garibay GR, Osorio A, Santamariña M, Ramón y Cajal T, et al. About 1% of the breast and ovarian Spanish families testing negative for BRCA1 and BRCA2 are carriers of RAD51D pathogenic variants. Int J Cancer. 2014;134:2088–97.
Ollier M, Radosevic-Robin N, Kwiatkowski F, Ponelle F, Viala S, Privat M, et al. DNA repair genes implicated in triple negative familial non-BRCA1/2 breast cancer predisposition. Am J Cancer Res. 2015;5:2113–26.
Daly MB, Pilarski R, Berry M, Buys SS, Farmer M, Friedman S, et al. NCCN guidelines insights: genetic/familial high-risk assessment: breast and ovarian, version 2.2017. J Natl Compr Canc Netw. 2017;15:9–20.
Banerjee S, Kaye SB, Ashworth A. Making the best of PARP inhibitors in ovarian cancer. Nat Rev Clin Oncol. 2010;7:508–19.
We thank the patients and their families for their participation in this study.
Conflict of interest
The authors declare that they have no conflict of interest.
About this article
Cite this article
Konstanta, I., Fostira, F., Apostolou, P. et al. Contribution of RAD51D germline mutations in breast and ovarian cancer in Greece. J Hum Genet 63, 1149–1158 (2018). https://doi.org/10.1038/s10038-018-0498-8