<div><h3>Background</h3>Although inherited breast cancer has been associated with germline mutations in genes that are functionally involved in the DNA homologous recombination repair (HRR) pathway, including BRCA1, BRCA2, TP53, ATM, BRIP1, CHEK2 and PALB2, about 70% of breast cancer heritability remains unexplained. Because of their critical functions in maintaining genome integrity and already well-established associations with breast cancer susceptibility, it is likely that additional genes involved in the HRR pathway harbor sequence variants associated with increased risk of breast cancer. RAD51 plays a central biological function in DNA repair and despite the fact that rare, likely dysfunctional variants in three of its five paralogs, RAD51C, RAD51D, and XRCC2, have been associated with breast and/or ovarian cancer risk, no population-based case-control mutation screening data are available for the RAD51 gene. We thus postulated that RAD51 could harbor rare germline mutations that confer increased risk of breast cancer. <h3>Methodology/Principal Findings</h3>We screened the coding exons and proximal splice junction regions of the gene for germline sequence variation in 1,330 early-onset breast cancer cases and 1,123 controls from the Breast Cancer Family Registry, using the same population-based sampling and analytical strategy that we developed for assessment of rare sequence variants in ATM and CHEK2. In total, 12 distinct very rare or private variants were characterized in RAD51, with 10 cases (0.75%) and 9 controls (0.80%) carrying such a variant. Variants were either likely neutral missense substitutions (3), silent substitutions (4) or non-coding substitutions (5) that were predicted to have little effect on efficiency of the splicing machinery. <h3>Conclusion</h3>Altogether, our data suggest that RAD51 tolerates so little dysfunctional sequence variation that rare variants in the gene contribute little, if anything, to breast cancer susceptibility. </div

Breast Cancer Family Registry (107256)

Catherine Voegele (107245)

Esther M. John (107266)

Fabienne Lesueur (10534)

Florence Le Calvez-Kelm (107221)

Francesca Damiola (5331)

Geoffroy Durand (107242)

Graham Byrnes (66091)

Irene L. Andrulis (107262)

Javier Oliver (107225)

John L. Hopper (89919)

Maxime P. Vallée (107250)

Melissa C. Southey (89921)

Nathalie Forey (107231)

Nivonirina Robinot (107236)

Sean V. Tavtigian (15066)

PubMed

Although inherited breast cancer has been associated with germline mutations in genes that are functionally involved in the DNA homologous recombination repair (HRR) pathway, including BRCA1, BRCA2, TP53, ATM, BRIP1, CHEK2 and PALB2, about 70% of breast cancer heritability remains unexplained. Because of their critical functions in maintaining genome integrity and already well-established associations with breast cancer susceptibility, it is likely that additional genes involved in the HRR pathway harbor sequence variants associated with increased risk of breast cancer. RAD51 plays a central biological function in DNA repair and despite the fact that rare, likely dysfunctional variants in three of its five paralogs, RAD51C, RAD51D, and XRCC2, have been associated with breast and/or ovarian cancer risk, no population-based case-control mutation screening data are available for the RAD51 gene. We thus postulated that RAD51 could harbor rare germline mutations that confer increased risk of breast cancer.We screened the coding exons and proximal splice junction regions of the gene for germline sequence variation in 1,330 early-onset breast cancer cases and 1,123 controls from the Breast Cancer Family Registry, using the same population-based sampling and analytical strategy that we developed for assessment of rare sequence variants in ATM and CHEK2. In total, 12 distinct very rare or private variants were characterized in RAD51, with 10 cases (0.75%) and 9 controls (0.80%) carrying such a variant. Variants were either likely neutral missense substitutions (3), silent substitutions (4) or non-coding substitutions (5) that were predicted to have little effect on efficiency of the splicing machinery.Altogether, our data suggest that RAD51 tolerates so little dysfunctional sequence variation that rare variants in the gene contribute little, if anything, to breast cancer susceptibility

Florence Le Calvez-Kelm

Javier Oliver

Francesca Damiola

Nathalie Forey

Nivonirina Robinot

Geoffroy Durand

Catherine Voegele

Maxime P Vallée

Graham Byrnes

Breast Cancer Family Registry

John L Hopper

Melissa C Southey

Irene L Andrulis

Esther M John

Sean V Tavtigian

Fabienne Lesueur

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RAD51 and breast cancer susceptibility: no evidence for rare variant association in the Breast Cancer Family Registry study.

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RAD51 and Breast Cancer Susceptibility: No Evidence for Rare Variant Association in the Breast Cancer Family Registry Study

A Laboratory Information Management System (LIMS) for a high throughput genetic platform aimed at candidate gene mutation screening.

A method and server for predicting damaging missense mutations.

A mutation in mouse rad51 results in an early embryonic lethal that is suppressed by a mutation in p53.

A PALB2 mutation associated with high risk of breast cancer.

A single nucleotide polymorphism in the RAD51 gene modifies cancer risk in BRCA2 but not BRCA1 carriers.

A single-nucleotide polymorphism in the RAD51 gene modifies breast cancer risk in BRCA2 carriers, but not in BRCA1 carriers or noncarriers.

Accounting for human polymorphisms predicted to affect protein function.

Altered DNA binding by the human Rad51-R150Q mutant found in breast cancer patients.

ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles.

Basic local alignment search tool.

BRCA2 germline mutations in male breast cancer cases and breast cancer families.

Description and validation of high-throughput simultaneous genotyping and mutation scanning by high-resolution melting curve analysis.

Determining the effectiveness of High Resolution Melting analysis for SNP genotyping and mutation scanning at the TP53 locus.

DNA double-strand breaks: signaling, repair and the cancer connection.

Enhancement of RAD51 recombinase activity by the tumor suppressor PALB2.

Full-length archaeal Rad51 structure and mutants: mechanisms for RAD51 assembly and control by BRCA2.

Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium.

Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms.

Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene.

Germline mutations in RAD51D confer susceptibility to ovarian cancer.

Identification of a novel human Rad51 variant that promotes DNA strand exchange.

Identification of Rad51 alteration in patients with bilateral breast cancer.

Improved splice site detection in Genie.

In silico analysis of missense substitutions using sequence-alignment based methods.

Insights into DNA recombination from the structure of a RAD51-BRCA2 complex.

Is RAD51 135G.C polymorphism really associated with breast cancer in general population? Biased design and results lead to inappropriate conclusion. Breast Cancer Res Treat 128: 297–299; author reply 300.

Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations.

M-Coffee: combining multiple sequence alignment methods with T-Coffee.

Maximum entropy modeling of short sequence motifs with applications to RNA splicing signals.

Molecular views of recombination proteins and their control.

Need for clarification of data in the recent meta-analysis about RAD51 135G.C polymorphism and breast cancer risk. Breast Cancer Res Treat 129: 649–651; author reply 652–

Overexpression of wild-type Rad51 correlates with histological grading of invasive ductal breast cancer.

p53 is linked directly to homologous recombination processes via RAD51/RecA protein interaction.

PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene.

Penetrance analysis of the PALB2 c.1592delT founder mutation.

PHYLIP - Phylogeny Inference Package (version 3.2).

RAD51 135G–.C modifies breast cancer risk among BRCA2 mutation carriers: results from a combined analysis of 19 studies.

RAD51 135G.C does not modify breast cancer risk in non-BRCA1/2 mutation carriers: evidence from a meta-analysis of 12 studies.

RAD51 135G.C polymorphism contributes to breast cancer susceptibility: a meta-analysis involving 26,444 subjects.

RAD51 135G/C polymorphism and breast cancer risk: a meta-analysis from 21 studies.

RAD51 G135C polymorphism is associated with breast cancer susceptibility: a meta-analysis involving 22,399 subjects.

RAD51 interacts with the evolutionarily conserved BRC motifs in the human breast cancer susceptibility gene brca2.

RAD51C germline mutations in breast and ovarian cancer patients.

Rare variants in the ATM gene and risk of breast cancer.

Rare, evolutionarily unlikely missense substitutions in ATM confer increased risk of breast cancer.

Rare, evolutionarily unlikely missense substitutions in CHEK2 contribute to breast cancer susceptibility: results from a breast cancer family registry casecontrol mutation-screening study.

Risks of cancer in BRCA1-mutation carriers. Breast Cancer Linkage Consortium.

Screening for RAD51 and BRCA2 BRC repeat mutations in breast and ovarian cancer families.

Screening RAD51C nucleotide alterations in patients with a family history of breast and ovarian cancer.

Targeted disruption of the Rad51 gene leads to lethality in embryonic mice.

The BRC repeats in BRCA2 are critical for RAD51 binding and resistance to methyl methanesulfonate treatment.

The Breast Cancer Family Registry: an infrastructure for cooperative multinational, interdisciplinary and translational studies of the genetic epidemiology of breast cancer.

Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles.

Variation in the RAD51 gene and familial breast cancer.

<em>RAD51</em> and Breast Cancer Susceptibility: No Evidence for Rare Variant Association in the Breast Cancer Family Registry Study

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