About 1% of the breast and ovarian Spanish families testing negative for BRCA1 and BRCA2 are carriers of RAD51D pathogenic variants

Gutiérrez‐Enríquez, Sara; Bonache, Sandra; Garibay, Gorka Ruíz de; Osorio, Ana; Santamariña, Marta; Cajal, Teresa Ramón y; Esteban-Cardeñosa, Eva; Tenés, Anna; Yanowsky, Kira; Barroso, Alicia; Montalban, Gemma; Blanco, Ana; Cornet, Mónica; Gadea, Neus; Infante, Mar; Caldés, Trinidad; Dı́az-Rubio, Eduardo; Balmañà, Judith; Lasa, Adriana; Vega, Ana; Benı́tez, Javier; Hoya, Miguel de la; Díez, Orland

doi:10.1002/ijc.28540

Cited by 25 publications

(11 citation statements)

References 28 publications

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“…The role of RAD51D mutations in breast cancer risk remains unresolved (3,4,45,46), and a possible involvement of RAD51D specifically in TNBC seems plausible (47). Our results do not support an association between c.620C>T;p.S207L and breast cancer in FCs although our study has limited power to rule out such an association.…”

contrasting

confidence: 81%

Functionally Null RAD51D Missense Mutation Associates Strongly with Ovarian Carcinoma

et al. 2017

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RAD51D is a key player in DNA repair by homologous recombination (HR), and truncating variant carriers have an increased risk for ovarian cancer. However, the contribution of nontruncating variants to cancer predisposition remains uncertain. Using deep sequencing and case-control genotyping studies, we show that in French Canadians, the missense variant c.620C>T;p.S207L is highly prevalent and is associated with a significantly increased risk for ovarian high-grade serous carcinoma (HGSC; 3.8% cases vs. 0.2% controls). The frequency of the p.S207L variant did not significantly differ from that of controls in breast, endometrial, pancreas, or colorectal adenocarcinomas. Functionally, we show that this mutation impairs HR by disrupting the RAD51D-XRCC2 interaction and confers PARP inhibitor sensitivity. These results highlight the importance of a functional RAD51D-XRCC2 interaction to promote HR and prevent the development of HGSC. This study identifies c.620C>T;p.S207L as the first bona fide pathogenic missense cancer susceptibility allele and supports the use of targeted PARP-inhibitor therapies in ovarian cancer patients carrying deleterious missense variants. .

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contrasting

confidence: 81%

Functionally Null RAD51D Missense Mutation Associates Strongly with Ovarian Carcinoma

et al. 2017

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“…The second rare missense variant c.947A>G (p.H316R) was novel; however, both these alterations in RAD51C were predicted as non-pathogenic. The only rare variant- c.629C>T (p.A210V)—in RAD51D was described previously [ 18 ] and was predicted as pathogenic ( Table 2 ).…”

Section: Resultsmentioning

confidence: 91%

“…A study by Loveday et al reported that germline mutations in the RAD51D gene (MIM:602954) confer susceptibility to OC in 0.9% of HBOC families (predominantly with more than one case of OC) and estimated the relative risk (RR) at 6.3 for OC and 1.32 for BC [ 14 ]. Several other studies have confirmed its role in OC susceptibility [ 15 , 16 , 17 , 18 ].…”

Section: Introductionmentioning

confidence: 78%

“…The earlier diagnosed patient died of OC dissemination 10 years after the diagnosis. This variant was previously described in Spanish and American HBOC patients [ 18 , 16 ]. A novel RAD51D mutation, c.879delG (p.C294Vfs*16), was found in an OC patient with a daughter suffering from BC and OC duplicity.…”

Section: Resultsmentioning

confidence: 98%

“…In our study, only one proband, carrying the pathogenic RAD51C mutation, displayed family cancer history that included OC and BC cases. Since previous studies reported no increased risk of BC for the carriers, later studies described few RAD51C and RAD51D truncating mutations in BC only families [ 13 , 27 , 28 , 18 , 24 ]. Although these mutations seem to be very rare in BC patients, they are probably responsible for certain BC predisposition.…”

Section: Discussionmentioning

confidence: 99%

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Mutation Analysis of the RAD51C and RAD51D Genes in High-Risk Ovarian Cancer Patients and Families from the Czech Republic

et al. 2015

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Recent studies have conferred that the RAD51C and RAD51D genes, which code for the essential proteins involved in homologous recombination, are ovarian cancer (OC) susceptibility genes that may explain genetic risks in high-risk patients. We performed a mutation analysis in 171 high-risk BRCA1 and BRCA2 negative OC patients, to evaluate the frequency of hereditary RAD51C and RAD51D variants in Czech population. The analysis involved direct sequencing, high resolution melting and multiple ligation-dependent probe analysis. We identified two (1.2%) and three (1.8%) inactivating germline mutations in both respective genes, two of which (c.379_380insG, p.P127Rfs*28 in RAD51C and c.879delG, p.C294Vfs*16 in RAD51D) were novel. Interestingly, an indicative family cancer history was not present in four carriers. Moreover, the ages at the OC diagnoses in identified mutation carriers were substantially lower than those reported in previous studies (four carriers were younger than 45 years). Further, we also described rare missense variants, two in RAD51C and one in RAD51D whose clinical significance needs to be verified. Truncating mutations and rare missense variants ascertained in OC patients were not detected in 1226 control samples. Although the cumulative frequency of RAD51C and RAD51D truncating mutations in our patients was lower than that of the BRCA1 and BRCA2 genes, it may explain OC susceptibility in approximately 3% of high-risk OC patients. Therefore, an RAD51C and RAD51D analysis should be implemented into the comprehensive multi-gene testing for high-risk OC patients, including early-onset OC patients without a family cancer history.

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A decade of RAD51C and RAD51D germline variants in cancer

et al. 2021

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Defects in DNA repair genes have been extensively associated with cancer susceptibility. Germline pathogenic variants (GPV) in genes involved in homologous recombination repair pathways predispose to cancers arising mainly in the breast and ovary, but also other tissues. The RAD51 paralogs RAD51C and RAD51D were included in this group 10 years ago when germline variants were associated with non-BRCA1/2 familial ovarian cancer. Here, we have reviewed the landscape of RAD51C and RAD51D germline variants in cancer reported in the literature during the last decade, integrating this list with variants identified by in-house patient screening. A comprehensive catalog of 341 variants that have been classified applying ACMG/AMP criteria has been generated pinpointing the existence of recurrent variants in both genes. Recurrent variants have been extensively discussed compiling data on population frequencies and functional characterization if available, highlighting variants that have not been fully characterized yet to properly establish their pathogenicity. Finally, we have complemented this data with relevant information regarding the conservation of mutated residues among RAD51 paralogs and modeling of putative hotspot areas, which contributes to generating an exhaustive update on these two cancer predisposition genes.

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About 1% of the breast and ovarian Spanish families testing negative for BRCA1 and BRCA2 are carriers of RAD51D pathogenic variants

Cited by 25 publications

References 28 publications

Functionally Null RAD51D Missense Mutation Associates Strongly with Ovarian Carcinoma

Functionally Null RAD51D Missense Mutation Associates Strongly with Ovarian Carcinoma

Mutation Analysis of the RAD51C and RAD51D Genes in High-Risk Ovarian Cancer Patients and Families from the Czech Republic

A decade of RAD51C and RAD51D germline variants in cancer

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