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101. Detecting differential allelic expression using high-resolution melting curve analysis: application to the breast cancer susceptibility gene CHEK2

Author

Sinilnikova Olga, McKay-Chopin Sandrine, Forey Nathalie, Michelon Jocelyne, Jordheim Lars P, Nguyen-Dumont Tú, Le Calvez-Kelm Florence, Southey Melissa C, Tavtigian Sean V, and Lesueur Fabienne

Subjects
Internal medicine, RC31-1245, Genetics, QH426-470
Abstract

Abstract Background The gene CHEK2 encodes a checkpoint kinase playing a key role in the DNA damage pathway. Though CHEK2 has been identified as an intermediate breast cancer susceptibility gene, only a small proportion of high-risk families have been explained by genetic variants located in its coding region. Alteration in gene expression regulation provides a potential mechanism for generating disease susceptibility. The detection of differential allelic expression (DAE) represents a sensitive assay to direct the search for a functional sequence variant within the transcriptional regulatory elements of a candidate gene. We aimed to assess whether CHEK2 was subject to DAE in lymphoblastoid cell lines (LCLs) from high-risk breast cancer patients for whom no mutation in BRCA1 or BRCA2 had been identified. Methods We implemented an assay based on high-resolution melting (HRM) curve analysis and developed an analysis tool for DAE assessment. Results We observed allelic expression imbalance in 4 of the 41 LCLs examined. All four were carriers of the truncating mutation 1100delC. We confirmed previous findings that this mutation induces non-sense mediated mRNA decay. In our series, we ruled out the possibility of a functional sequence variant located in the promoter region or in a regulatory element of CHEK2 that would lead to DAE in the transcriptional regulatory milieu of freely proliferating LCLs. Conclusions Our results support that HRM is a sensitive and accurate method for DAE assessment. This approach would be of great interest for high-throughput mutation screening projects aiming to identify genes carrying functional regulatory polymorphisms.

Published
2011
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102. Determining the effectiveness of High Resolution Melting analysis for SNP genotyping and mutation scanning at the TP53 locus

Author

De Silva Deepika, Le Calvez-Kelm Florence, Nguyen-Dumont Tú, Voegele Catherine, Gemignani Federica, Garritano Sonia, Lesueur Fabienne, Landi Stefano, and Tavtigian Sean V

Subjects
Genetics, QH426-470
Abstract

Abstract Background Together single nucleotide substitutions and small insertion/deletion variants are the most common form of sequence variation in the human gene pool. High-resolution SNP profile and/or haplotype analyses enable the identification of modest-risk susceptibility genes to common diseases, genes that may modulate responses to pharmaceutical agents, and SNPs that can affect either their expression or function. In addition, sensitive techniques for germline or somatic mutation detection are important tools for characterizing sequence variations in genes responsible for tumor predisposition. Cost-effective methods are highly desirable. Many of the recently developed high-throughput technologies are geared toward industrial scale genetic studies and arguably do not provide useful solutions for small laboratory investigator-initiated projects. Recently, the use of new fluorescent dyes allowed the high-resolution analysis of DNA melting curves (HRM). Results Here, we compared the capacity of HRM, applicable to both genotyping and mutation scanning, to detect genetic variations in the tumor suppressor gene TP53 with that of mutation screening by full resequencing. We also assessed the performance of a variety of available HRM-based genotyping assays by genotyping 30 TP53 SNPs. We describe a series of solutions to handle the difficulties that may arise in large-scale application of HRM to mutation screening and genotyping at the TP53 locus. In particular, we developed specific HRM assays that render possible genotyping of 2 or more, sometimes closely spaced, polymorphisms within the same amplicon. We also show that simultaneous genotyping of 2 SNPs from 2 different amplicons using a multiplex PCR reaction is feasible; the data can be analyzed in a single HRM run, potentially improving the efficiency of HRM genotyping workflows. Conclusion The HRM technique showed high sensitivity and specificity (1.0, and 0.8, respectively, for amplicons of

Published
2009
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103. Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification

Author

Parsons, Michael T., Tudini, Emma, Li, Hongyan, Hahnen, Eric, Wappenschmidt, Barbara, Feliubadalo, Lidia, Aalfs, Cora M., Agata, Simona, Aittomaki, Kristiina, Alducci, Elisa, Concepcion Alonso-Cerezo, Maria, Arnold, Norbert, Auber, Bernd, Austin, Rachel, Azzollini, Jacopo, Balmana, Judith, Barbieri, Elena, Bartram, Claus R., Blanco, Ana, Bluemcke, Britta, Bonache, Sandra, Bonanni, Bernardo, Borg, Ake, Bortesi, Beatrice, Brunet, Joan, Bruzzone, Carla, Bucksch, Karolin, Cagnoli, Giulia, Caldes, Trinidad, Caliebe, Almuth, Caligo, Maria A., Calvello, Mariarosaria, Capone, Gabriele L., Caputo, Sandrine M., Carnevali, Ileana, Carrasco, Estela, Caux-Moncoutier, Virginie, Cavalli, Pietro, Cini, Giulia, Clarke, Edward M., Concolino, Paola, Cops, Elisa J., Cortesi, Laura, Couch, Fergus J., Darder, Esther, de la Hoya, Miguel, Dean, Michael, Debatin, Irmgard, Del Valle, Jesus, Delnatte, Capucine, Derive, Nicolas, Diez, Orland, Ditsch, Nina, Domchek, Susan M., Dutrannoy, Veronique, Eccles, Diana M., Ehrencrona, Hans, Enders, Ute, Evans, D. Gareth, Farra, Chantal, Faust, Ulrike, Felbor, Ute, Feroce, Irene, Fine, Miriam, Foulkes, William D., Galvao, Henrique Cr, Gambino, Gaetana, Gehrig, Andrea, Gensini, Francesca, Gerdes, Anne-Marie, Germani, Aldo, Giesecke, Jutta, Gismondi, Viviana, Gomez, Carolina, Garcia, Encarna B. Gomez, Gonzalez, Sara, Grau, Elia, Grill, Sabine, Gross, Eva, Guerrieri-Gonzaga, Aliana, Guillaud-Bataille, Marine, Gutierrez-Enriquez, Sara, Haaf, Thomas, Hackmann, Karl, Hansen, Thomas Vo, Harris, Marion, Hauke, Jan, Heinrich, Tilman, Hellebrand, Heide, Herold, Karen N., Honisch, Ellen, Horvath, Judit, Houdayer, Claude, Huebbel, Verena, Iglesias, Silvia, Izquierdo, Angel, James, Paul A., Janssen, Linda Am, Jeschke, Udo, Kaulfuss, Silke, Keupp, Katharina, Kiechle, Marion, Koelbl, Alexandra, Krieger, Sophie, Kruse, Torben A., Kvist, Anders, Lalloo, Fiona, Larsen, Mirjam, Lattimore, Vanessa L., Lautrup, Charlotte, Ledig, Susanne, Leinert, Elena, Lewis, Alexandra L., Lim, Joanna, Loeffler, Markus, Lopez-Fernandez, Adria, Lucci-Cordisco, Emanuela, Maass, Nicolai, Manoukian, Siranoush, Marabelli, Monica, Matricardi, Laura, Meindl, Alfons, Michelli, Rodrigo D., Moghadasi, Setareh, Moles-Fernandez, Alejandro, Montagna, Marco, Montalban, Gemma, Monteiro, Alvaro N., Montes, Eva, Mori, Luigi, Moserle, Lidia, Mueller, Clemens R., Mundhenke, Christoph, Naldi, Nadia, Nathanson, Katherine L., Navarro, Matilde, Nevanlinna, Heli, Nichols, Cassandra B., Niederacher, Dieter, Nielsen, Henriette R., Ong, Kai-ren, Pachter, Nicholas, Palmero, Edenir, I, Papi, Laura, Pedersen, Inge Sokilde, Peissel, Bernard, Perez-Segura, Pedro, Pfeifer, Katharina, Pineda, Marta, Pohl-Rescigno, Esther, Poplawski, Nicola K., Porfirio, Berardino, Quante, Anne S., Ramser, Juliane, Reis, Rui M., Revillion, Francoise, Rhiem, Kerstin, Riboli, Barbara, Ritter, Julia, Rivera, Daniela, Rofes, Paula, Rump, Andreas, Salinas, Monica, Sanchez de Abajo, Ana Maria, Schmidt, Gunnar, Schoenwiese, Ulrike, Seggewiss, Jochen, Solanes, Ares, Steinemann, Doris, Stiller, Mathias, Stoppa-Lyonnet, Dominique, Sullivan, Kelly J., Susman, Rachel, Sutter, Christian, Tavtigian, Sean, V, Teo, Soo H., Teule, Alex, Thomassen, Mads, Tibiletti, Maria Grazia, Tischkowitz, Marc, Tognazzo, Silvia, Toland, Amanda E., Tornero, Eva, Torngren, Therese, Torres-Esquius, Sara, Toss, Angela, Trainer, Alison H., Tucker, Katherine M., van Asperen, Christi J., van Mackelenbergh, Marion T., Varesco, Liliana, Vargas-Parra, Gardenia, Varon, Raymonda, Vega, Ana, Velasco, Angela, Vesper, Anne-Sophie, Viel, Alessandra, Vreeswijk, Maaike P. G., Wagner, Sebastian A., Waha, Anke, Walker, Logan C., Walters, Rhiannon J., Wang-Gohrke, Shan, Weber, Bernhard H. F., Weichert, Wilko, Wieland, Kerstin, Wiesmueller, Lisa, Witzel, Isabell, Woeckel, Achim, Woodward, Emma R., Zachariae, Silke, Zampiga, Valentina, Zeder-Goss, Christine, Lazaro, Conxi, De Nicolo, Arcangela, Radice, Paolo, Engel, Christoph, Schmutzler, Rita K., Goldgar, David E., Spurdle, Amanda B., Parsons, Michael T., Tudini, Emma, Li, Hongyan, Hahnen, Eric, Wappenschmidt, Barbara, Feliubadalo, Lidia, Aalfs, Cora M., Agata, Simona, Aittomaki, Kristiina, Alducci, Elisa, Concepcion Alonso-Cerezo, Maria, Arnold, Norbert, Auber, Bernd, Austin, Rachel, Azzollini, Jacopo, Balmana, Judith, Barbieri, Elena, Bartram, Claus R., Blanco, Ana, Bluemcke, Britta, Bonache, Sandra, Bonanni, Bernardo, Borg, Ake, Bortesi, Beatrice, Brunet, Joan, Bruzzone, Carla, Bucksch, Karolin, Cagnoli, Giulia, Caldes, Trinidad, Caliebe, Almuth, Caligo, Maria A., Calvello, Mariarosaria, Capone, Gabriele L., Caputo, Sandrine M., Carnevali, Ileana, Carrasco, Estela, Caux-Moncoutier, Virginie, Cavalli, Pietro, Cini, Giulia, Clarke, Edward M., Concolino, Paola, Cops, Elisa J., Cortesi, Laura, Couch, Fergus J., Darder, Esther, de la Hoya, Miguel, Dean, Michael, Debatin, Irmgard, Del Valle, Jesus, Delnatte, Capucine, Derive, Nicolas, Diez, Orland, Ditsch, Nina, Domchek, Susan M., Dutrannoy, Veronique, Eccles, Diana M., Ehrencrona, Hans, Enders, Ute, Evans, D. Gareth, Farra, Chantal, Faust, Ulrike, Felbor, Ute, Feroce, Irene, Fine, Miriam, Foulkes, William D., Galvao, Henrique Cr, Gambino, Gaetana, Gehrig, Andrea, Gensini, Francesca, Gerdes, Anne-Marie, Germani, Aldo, Giesecke, Jutta, Gismondi, Viviana, Gomez, Carolina, Garcia, Encarna B. Gomez, Gonzalez, Sara, Grau, Elia, Grill, Sabine, Gross, Eva, Guerrieri-Gonzaga, Aliana, Guillaud-Bataille, Marine, Gutierrez-Enriquez, Sara, Haaf, Thomas, Hackmann, Karl, Hansen, Thomas Vo, Harris, Marion, Hauke, Jan, Heinrich, Tilman, Hellebrand, Heide, Herold, Karen N., Honisch, Ellen, Horvath, Judit, Houdayer, Claude, Huebbel, Verena, Iglesias, Silvia, Izquierdo, Angel, James, Paul A., Janssen, Linda Am, Jeschke, Udo, Kaulfuss, Silke, Keupp, Katharina, Kiechle, Marion, Koelbl, Alexandra, Krieger, Sophie, Kruse, Torben A., Kvist, Anders, Lalloo, Fiona, Larsen, Mirjam, Lattimore, Vanessa L., Lautrup, Charlotte, Ledig, Susanne, Leinert, Elena, Lewis, Alexandra L., Lim, Joanna, Loeffler, Markus, Lopez-Fernandez, Adria, Lucci-Cordisco, Emanuela, Maass, Nicolai, Manoukian, Siranoush, Marabelli, Monica, Matricardi, Laura, Meindl, Alfons, Michelli, Rodrigo D., Moghadasi, Setareh, Moles-Fernandez, Alejandro, Montagna, Marco, Montalban, Gemma, Monteiro, Alvaro N., Montes, Eva, Mori, Luigi, Moserle, Lidia, Mueller, Clemens R., Mundhenke, Christoph, Naldi, Nadia, Nathanson, Katherine L., Navarro, Matilde, Nevanlinna, Heli, Nichols, Cassandra B., Niederacher, Dieter, Nielsen, Henriette R., Ong, Kai-ren, Pachter, Nicholas, Palmero, Edenir, I, Papi, Laura, Pedersen, Inge Sokilde, Peissel, Bernard, Perez-Segura, Pedro, Pfeifer, Katharina, Pineda, Marta, Pohl-Rescigno, Esther, Poplawski, Nicola K., Porfirio, Berardino, Quante, Anne S., Ramser, Juliane, Reis, Rui M., Revillion, Francoise, Rhiem, Kerstin, Riboli, Barbara, Ritter, Julia, Rivera, Daniela, Rofes, Paula, Rump, Andreas, Salinas, Monica, Sanchez de Abajo, Ana Maria, Schmidt, Gunnar, Schoenwiese, Ulrike, Seggewiss, Jochen, Solanes, Ares, Steinemann, Doris, Stiller, Mathias, Stoppa-Lyonnet, Dominique, Sullivan, Kelly J., Susman, Rachel, Sutter, Christian, Tavtigian, Sean, V, Teo, Soo H., Teule, Alex, Thomassen, Mads, Tibiletti, Maria Grazia, Tischkowitz, Marc, Tognazzo, Silvia, Toland, Amanda E., Tornero, Eva, Torngren, Therese, Torres-Esquius, Sara, Toss, Angela, Trainer, Alison H., Tucker, Katherine M., van Asperen, Christi J., van Mackelenbergh, Marion T., Varesco, Liliana, Vargas-Parra, Gardenia, Varon, Raymonda, Vega, Ana, Velasco, Angela, Vesper, Anne-Sophie, Viel, Alessandra, Vreeswijk, Maaike P. G., Wagner, Sebastian A., Waha, Anke, Walker, Logan C., Walters, Rhiannon J., Wang-Gohrke, Shan, Weber, Bernhard H. F., Weichert, Wilko, Wieland, Kerstin, Wiesmueller, Lisa, Witzel, Isabell, Woeckel, Achim, Woodward, Emma R., Zachariae, Silke, Zampiga, Valentina, Zeder-Goss, Christine, Lazaro, Conxi, De Nicolo, Arcangela, Radice, Paolo, Engel, Christoph, Schmutzler, Rita K., Goldgar, David E., and Spurdle, Amanda B.

Abstract

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification.

Published
2019

104. Mutation analysis and characterization of ATR sequence variants in breast cancer cases from high-risk French Canadian breast/ovarian cancer families

Author

Pichette Roxane, Ouellette Geneviève, Lespérance Bernard, Lépine Jean, Laframboise Rachel, Chiquette Jocelyne, Labuda Damian, Bessette Paul, Sinilnikova Olga, Soucy Penny, Labrie Yvan, Durocher Francine, Plante Marie, Tavtigian Sean V, and Simard Jacques

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Ataxia telangiectasia-mutated and Rad3-related (ATR) is a member of the PIK-related family which plays, along with ATM, a central role in cell-cycle regulation. ATR has been shown to phosphorylate several tumor suppressors like BRCA1, CHEK1 and TP53. ATR appears as a good candidate breast cancer susceptibility gene and the current study was designed to screen for ATR germline mutations potentially involved in breast cancer predisposition. Methods ATR direct sequencing was performed using a fluorescent method while widely available programs were used for linkage disequilibrium (LD), haplotype analyses, and tagging SNP (tSNP) identification. Expression analyses were carried out using real-time PCR. Results The complete sequence of all exons and flanking intronic sequences were analyzed in DNA samples from 54 individuals affected with breast cancer from non-BRCA1/2 high-risk French Canadian breast/ovarian families. Although no germline mutation has been identified in the coding region, we identified 41 sequence variants, including 16 coding variants, 3 of which are not reported in public databases. SNP haplotypes were established and tSNPs were identified in 73 healthy unrelated French Canadians, providing a valuable tool for further association studies involving the ATR gene, using large cohorts. Our analyses led to the identification of two novel alternative splice transcripts. In contrast to the transcript generated by an alternative splicing site in the intron 41, the one resulting from a deletion of 121 nucleotides in exon 33 is widely expressed, at significant but relatively low levels, in both normal and tumoral cells including normal breast and ovarian tissue. Conclusion Although no deleterious mutations were identified in the ATR gene, the current study provides an haplotype analysis of the ATR gene polymorphisms, which allowed the identification of a set of SNPs that could be used as tSNPs for large-scale association studies. In addition, our study led to the characterization of a novel Δ33 splice form, which could generate a putative truncated protein lacking several functional domains. Additional studies in large cohorts and other populations will be needed to further evaluate if common and/or rare ATR sequence variants can be associated with a modest or intermediate breast cancer risk.

Published
2006
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108. A quantitative model to predict pathogenicity of missense variants in the TP53 gene

Author

Fortuno, Cristina, primary, Cipponi, Arcadi, additional, Ballinger, Mandy L., additional, Tavtigian, Sean V., additional, Olivier, Magali, additional, Ruparel, Vatsal, additional, Haupt, Ygal, additional, Haupt, Sue, additional, Study, International Sarcoma Kindred, additional, Tucker, Kathy, additional, Spurdle, Amanda B., additional, Thomas, David M., additional, and James, Paul A., additional

Published
2019
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110. Contribution of mRNA Splicing to Mismatch Repair Gene Sequence Variant Interpretation.

Author

Thompson, Bryony A., Walters, Rhiannon, Parsons, Michael T., Dumenil, Troy, Drost, Mark, Tiersma, Yvonne, Lindor, Noralane M., Tavtigian, Sean V., de Wind, Niels, Spurdle, Amanda B., Al-Mulla, Fahd, Buchanan, Daniel, Farrington, Susan, Frayling, Ian, Genuardi, Maurizio, Holinski-Feder, Elke, Kohonen-Corish, Maija R. J., Laner, Andreas, Martins, Alexandra, and Macrae, Finlay

Subjects
MESSENGER RNA, PROTEIN expression, GENES, HEREDITARY nonpolyposis colorectal cancer
Abstract

Functional assays that assess mRNA splicing can be used in interpretation of the clinical significance of sequence variants, including the Lynch syndrome-associated mismatch repair (MMR) genes. The purpose of this study was to investigate the contribution of splicing assay data to the classification of MMR gene sequence variants. We assayed mRNA splicing for 24 sequence variants in MLH1 , MSH2 , and MSH6 , including 12 missense variants that were also assessed using a cell-free in vitro MMR activity (CIMRA) assay. Multifactorial likelihood analysis was conducted for each variant, combining CIMRA outputs and clinical data where available. We collated these results with existing public data to provide a dataset of splicing assay results for a total of 671 MMR gene sequence variants (328 missense/in-frame indel), and published and unpublished repair activity measurements for 154 of these variants. There were 241 variants for which a splicing aberration was detected: 92 complete impact, 33 incomplete impact, and 116 where it was not possible to determine complete versus incomplete splicing impact. Splicing results mostly aided in the interpretation of intronic (72%) and silent (92%) variants and were the least useful for missense substitutions/in-frame indels (10%). MMR protein functional activity assays were more useful in the analysis of these exonic variants but by design they were not able to detect clinically important splicing aberrations identified by parallel mRNA assays. The development of high throughput assays that can quantitatively assess impact on mRNA transcript expression and protein function in parallel will streamline classification of MMR gene sequence variants. [ABSTRACT FROM AUTHOR]

Published
2020
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112. Association of Sulindac and Erlotinib vs Placebo With Colorectal Neoplasia in Familial Adenomatous Polyposis

Author

Samadder, N. Jewel, primary, Kuwada, Scott K., additional, Boucher, Kenneth M., additional, Byrne, Kathryn, additional, Kanth, Priyanka, additional, Samowitz, Wade, additional, Jones, David, additional, Tavtigian, Sean V., additional, Westover, Michelle, additional, Berry, Therese, additional, Jasperson, Kory, additional, Pappas, Lisa, additional, Smith, Laurel, additional, Sample, Danielle, additional, Burt, Randall W., additional, and Neklason, Deborah W., additional

Published
2018
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113. Assessment of the evidence yield for the calibrated PP3/BP4 computational recommendations

Author

Stenton, Sarah L., Pejaver, Vikas, Bergquist, Timothy, Biesecker, Leslie G., Byrne, Alicia B., Nadeau, Emily A.W., Greenblatt, Marc S., Harrison, Steven M., Tavtigian, Sean V., Radivojac, Predrag, Brenner, Steven E., O’Donnell-Luria, Anne, Biesecker, Leslie G., Harrison, Steven M., Tayoun, Ahmad A., Berg, Jonathan S., Brenner, Steven E., Cutting, Garry R., Ellard, Sian, Greenblatt, Marc S., Kang, Peter, Karbassi, Izabela, Karchin, Rachel, Mester, Jessica, O’Donnell-Luria, Anne, Pesaran, Tina, Plon, Sharon E., Rehm, Heidi L., Strande, Natasha T., Tavtigian, Sean V., and Topper, Scott

Abstract

: To investigate the number of rare missense variants observed in human genome sequences by ACMG/AMP PP3/BP4 evidence strength, following the calibrated PP3/BP4 computational recommendations.

Published
2024
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114. PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS

Author

Southey, Melissa C, Goldgar, David E, Winqvist, Robert, Pylkäs, Katri, Couch, Fergus, Tischkowitz, Marc, Foulkes, William D, Dennis, Joe, Michailidou, Kyriaki, van Rensburg, Elizabeth J, Heikkinen, Tuomas, Nevanlinna, Heli, Hopper, John L, Dörk, Thilo, Claes, Kathleen Bm, Reis-Filho, Jorge, Teo, Zhi Ling, Radice, Paolo, Catucci, Irene, Peterlongo, Paolo, Tsimiklis, Helen, Odefrey, Fabrice A, Dowty, James G, Schmidt, Marjanka K, Broeks, Annegien, Hogervorst, Frans B, Verhoef, Senno, Carpenter, Jane, Clarke, Christine, Scott, Rodney J, Fasching, Peter A, Haeberle, Lothar, Ekici, Arif B, Beckmann, Matthias W, Peto, Julian, Dos-Santos-Silva, Isabel, Fletcher, Olivia, Johnson, Nichola, Bolla, Manjeet K, Sawyer, Elinor J, Tomlinson, Ian, Kerin, Michael J, Miller, Nicola, Marme, Federik, Burwinkel, Barbara, Yang, Rongxi, Guénel, Pascal, Truong, Thérèse, Menegaux, Florence, Sanchez, Marie, Bojesen, Stig, Nielsen, Sune F, Flyger, Henrik, Benitez, Javier, Zamora, M Pilar, Perez, Jose Ignacio Arias, Menéndez, Primitiva, Anton-Culver, Hoda, Neuhausen, Susan, Ziogas, Argyrios, Clarke, Christina A, Brenner, Hermann, Arndt, Volker, Stegmaier, Christa, Brauch, Hiltrud, Brüning, Thomas, Ko, Yon-Dschun, Muranen, Taru A, Aittomäki, Kristiina, Blomqvist, Carl, Bogdanova, Natalia V, Antonenkova, Natalia N, Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, Hartikainen, Jaana M, Spurdle, Amanda B, Investigators, kConFab, Australian Ovarian Cancer Study Group, Wauters, Els, Smeets, Dominiek, Beuselinck, Benoit, Floris, Giuseppe, Chang-Claude, Jenny, Rudolph, Anja, Seibold, Petra, Flesch-Janys, Dieter, Olson, Janet E, Vachon, Celine, Pankratz, Vernon S, McLean, Catriona, Haiman, Christopher A, Henderson, Brian E, Schumacher, Fredrick, Le Marchand, Loic, Kristensen, Vessela, Alnæs, Grethe Grenaker, Zheng, Wei, Hunter, David J, Lindstrom, Sara, Hankinson, Susan E, Kraft, Peter, Andrulis, Irene, Knight, Julia A, Glendon, Gord, Mulligan, Anna Marie, Jukkola-Vuorinen, Arja, Grip, Mervi, Kauppila, Saila, Devilee, Peter, Tollenaar, Robert AEM, Seynaeve, Caroline, Hollestelle, Antoinette, Garcia-Closas, Montserrat, Figueroa, Jonine, Chanock, Stephen J, Lissowska, Jolanta, Czene, Kamila, Darabi, Hatef, Eriksson, Mikael, Eccles, Diana M, Rafiq, Sajjad, Tapper, William J, Gerty, Sue M, Hooning, Maartje J, Martens, John WM, Collée, J Margriet, Tilanus-Linthorst, Madeleine, Hall, Per, Li, Jingmei, Brand, Judith S, Humphreys, Keith, Cox, Angela, Reed, Malcolm WR, Luccarini, Craig, Baynes, Caroline, Dunning, Alison M, Hamann, Ute, Torres, Diana, Ulmer, Hans Ulrich, Rüdiger, Thomas, Jakubowska, Anna, Lubinski, Jan, Jaworska, Katarzyna, Durda, Katarzyna, Slager, Susan, Toland, Amanda E, Ambrosone, Christine B, Yannoukakos, Drakoulis, Swerdlow, Anthony, Ashworth, Alan, Orr, Nick, Jones, Michael, González-Neira, Anna, Pita, Guillermo, Alonso, M Rosario, Álvarez, Nuria, Herrero, Daniel, Tessier, Daniel C, Vincent, Daniel, Bacot, Francois, Simard, Jacques, Dumont, Martine, Soucy, Penny, Eeles, Rosalind, Muir, Kenneth, Wiklund, Fredrik, Gronberg, Henrik, Schleutker, Johanna, Nordestgaard, Børge G, Weischer, Maren, Travis, Ruth C, Neal, David, Donovan, Jenny L, Hamdy, Freddie C, Khaw, Kay-Tee, Stanford, Janet L, Blot, William J, Thibodeau, Stephen, Schaid, Daniel J, Kelley, Joseph L, Maier, Christiane, Kibel, Adam S, Cybulski, Cezary, Cannon-Albright, Lisa, Butterbach, Katja, Park, Jong, Kaneva, Radka, Batra, Jyotsna, Teixeira, Manuel R, Kote-Jarai, Zsofia, Olama, Ali Amin Al, Benlloch, Sara, Renner, Stefan P, Hartmann, Arndt, Hein, Alexander, Ruebner, Matthias, Lambrechts, Diether, Van Nieuwenhuysen, Els, Vergote, Ignace, Lambretchs, Sandrina, Doherty, Jennifer A, Rossing, Mary Anne, Nickels, Stefan, Eilber, Ursula, Wang-Gohrke, Shan, Odunsi, Kunle, Sucheston-Campbell, Lara E, Friel, Grace, Lurie, Galina, Killeen, Jeffrey L, Wilkens, Lynne R, Goodman, Marc T, Runnebaum, Ingo, Hillemanns, Peter A, Pelttari, Liisa M, Butzow, Ralf, Modugno, Francesmary, Edwards, Robert P, Ness, Roberta B, Moysich, Kirsten B, du Bois, Andreas, Heitz, Florian, Harter, Philipp, Kommoss, Stefan, Karlan, Beth Y, Walsh, Christine, Lester, Jenny, Jensen, Allan, Kjaer, Susanne Krüger, Høgdall, Estrid, Peissel, Bernard, Bonanni, Bernardo, Bernard, Loris, Goode, Ellen L, Fridley, Brooke L, Vierkant, Robert A, Cunningham, Julie M, Larson, Melissa C, Fogarty, Zachary C, Kalli, Kimberly R, Liang, Dong, Lu, Karen H, Hildebrandt, Michelle AT, Wu, Xifeng, Levine, Douglas A, Dao, Fanny, Bisogna, Maria, Berchuck, Andrew, Iversen, Edwin S, Marks, Jeffrey R, Akushevich, Lucy, Cramer, Daniel W, Schildkraut, Joellen, Terry, Kathryn L, Poole, Elizabeth M, Stampfer, Meir, Tworoger, Shelley S, Bandera, Elisa V, Orlow, Irene, Olson, Sara H, Bjorge, Line, Salvesen, Helga B, van Altena, Anne M, Aben, Katja KH, Kiemeney, Lambertus A, Massuger, Leon FAG, Pejovic, Tanja, Bean, Yukie, Brooks-Wilson, Angela, Kelemen, Linda E, Cook, Linda S, Le, Nhu D, Górski, Bohdan, Gronwald, Jacek, Menkiszak, Janusz, Høgdall, Claus K, Lundvall, Lene, Nedergaard, Lotte, Engelholm, Svend Aage, Dicks, Ed, Tyrer, Jonathan, Campbell, Ian, McNeish, Iain, Paul, James, Siddiqui, Nadeem, Glasspool, Rosalind, Whittemore, Alice S, Rothstein, Joseph H, McGuire, Valerie, Sieh, Weiva, Cai, Hui, Shu, Xiao-Ou, Teten, Rachel T, Sutphen, Rebecca, McLaughlin, John R, Narod, Steven A, Phelan, Catherine M, Monteiro, Alvaro N, Fenstermacher, David, Lin, Hui-Yi, Permuth, Jennifer B, Sellers, Thomas A, Chen, Y Ann, Tsai, Ya-Yu, Chen, Zhihua, Gentry-Maharaj, Aleksandra, Gayther, Simon A, Ramus, Susan J, Menon, Usha, Wu, Anna H, Pearce, Celeste L, Van Den Berg, David, Pike, Malcolm C, Dansonka-Mieszkowska, Agnieszka, Plisiecka-Halasa, Joanna, Moes-Sosnowska, Joanna, Kupryjanczyk, Jolanta, Pharoah, Paul Dp, Song, Honglin, Winship, Ingrid, Chenevix-Trench, Georgia, Giles, Graham G, Tavtigian, Sean V, Easton, Doug F, Milne, Roger L, Clinical Genetics, Neurology, Medical Oncology, Surgery, Erasmus MC other, Clinicum, Department of Obstetrics and Gynecology, Medicum, Kristiina Aittomäki / Principal Investigator, Department of Medical and Clinical Genetics, Department of Oncology, Department of Pathology, HUS Gynecology and Obstetrics, Tischkowitz, Marc [0000-0002-7880-0628], Dennis, Joe [0000-0003-4591-1214], Dunning, Alison [0000-0001-6651-7166], Khaw, Kay-Tee [0000-0002-8802-2903], Amin Al Olama, Ali [0000-0002-7178-3431], Dicks, Ed [0000-0002-0617-0401], Tyrer, Jonathan [0000-0003-3724-4757], Pharoah, Paul [0000-0001-8494-732X], Song, Honglin [0000-0001-5076-7371], Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Oncology, Male, Ataxia Telangiectasia Mutated Proteins, prostate-cancer, Prostate cancer, 0302 clinical medicine, brca1, Medizinische Fakultät, Medicine and Health Sciences, skin and connective tissue diseases, Genetics (clinical), Ovarian Neoplasms, education.field_of_study, brca2-interacting protein, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], 1184 Genetics, developmental biology, physiology, Nuclear Proteins, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], 3. Good health, PROSTATE-CANCER, Cancer: prostate, Multicenter Study, ovarian-cancer, Centre for Surgical Research, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], 030220 oncology & carcinogenesis, ovary [Cancer], Female, Fanconi Anemia Complementation Group N Protein, metaanalysis, Risk, medicine.medical_specialty, SUSCEPTIBILITY LOCI, Population, 3122 Cancers, cancer predisposition, Breast Neoplasms, OVARIAN-CANCER, BRCA2-INTERACTING PROTEIN, Cancer: ovary, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, prostate [Cancer], medicine, Cancer Genetics, Genetics, Journal Article, breast [Cancer], BREAST-CANCER, Humans, Genetic Predisposition to Disease, ddc:610, education, gene, CHEK2, FAMILY REGISTRY, METAANALYSIS, breast-cancer, Genetic Association Studies, business.industry, MUTATIONS, Cancer: breast, Tumor Suppressor Proteins, Case-control study, Cancer, Prostatic Neoplasms, medicine.disease, BRCA1, mutations, GENE, susceptibility loci, Checkpoint Kinase 2, 030104 developmental biology, Relative risk, Case-Control Studies, Mutation, family registry, Ovarian cancer, business
Abstract

Background: The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study.Methods: We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant.Results: For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10−5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10−8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants.Conclusions: This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.

Published
2016
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115. Universal Panel Testing of Pancreatic Cancer Cases for Cancer Predisposition

Author

Young, Erin L., primary, Thompson, Bryony A., additional, Neklason, Deborah W., additional, Snow, Angela K., additional, Firpo, Matthew A., additional, Werner, Theresa, additional, Bell, Russell, additional, Sutherland, Nykole R., additional, Smith, Ken R., additional, Berger, Justin, additional, Fraser, Alison, additional, Gammon, Amanda, additional, Koptiuch, Cathryn, additional, Kohlmann, Wendy K, additional, Neumayer, Leigh, additional, Goldgar, David E., additional, Mulvihill, Sean J., additional, Cannon-Albright, Lisa A., additional, and Tavtigian, Sean V., additional

Published
2017
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116. Abstract 2704: Pathogenic mutations and variants of unknown significance (VUS) in cancer predisposition genes are associated with over 10% of pediatric rhabdomyosarcoma: a report from the Children’s Oncology Group

Author

Young, Erin L., primary, Maese, Luke, additional, Robinson, Rosann, additional, Pflieger, Lance, additional, Moore, Barry, additional, Rynearson, Shawn, additional, Fowler, Trent, additional, Tavtigian, Sean V., additional, Yandell, Mark, additional, Mason, Clinton C., additional, Hawkins, Douglas S., additional, Lupo, Philip J., additional, and Schiffman, Joshua D., additional

Published
2017
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117. Recommendations for application of the functional evidence PS3/BS3 criterion using the ACMG/AMP sequence variant interpretation framework.

Author

Brnich, Sarah E., Abou Tayoun, Ahmad N., Couch, Fergus J., Cutting, Garry R., Greenblatt, Marc S., Heinen, Christopher D., Kanavy, Dona M., Luo, Xi, McNulty, Shannon M., Starita, Lea M., Tavtigian, Sean V., Wright, Matt W., Harrison, Steven M., Biesecker, Leslie G., Berg, Jonathan S., On behalf of the Clinical Genome Resource Sequence Variant Interpretation Working Group, Brenner, Steven E., Ellard, Sian, Karbassi, Izabela, and Karchin, Rachel

Subjects
MOLECULAR pathology, MEDICAL genetics, EVIDENCE, MEDICAL genomics, STATISTICS, VITAL statistics
Abstract

Background: The American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) clinical variant interpretation guidelines established criteria for different types of evidence. This includes the strong evidence codes PS3 and BS3 for "well-established" functional assays demonstrating a variant has abnormal or normal gene/protein function, respectively. However, they did not provide detailed guidance on how functional evidence should be evaluated, and differences in the application of the PS3/BS3 codes are a contributor to variant interpretation discordance between laboratories. This recommendation seeks to provide a more structured approach to the assessment of functional assays for variant interpretation and guidance on the use of various levels of strength based on assay validation. Methods: The Clinical Genome Resource (ClinGen) Sequence Variant Interpretation (SVI) Working Group used curated functional evidence from ClinGen Variant Curation Expert Panel-developed rule specifications and expert opinions to refine the PS3/BS3 criteria over multiple in-person and virtual meetings. We estimated the odds of pathogenicity for assays using various numbers of variant controls to determine the minimum controls required to reach moderate level evidence. Feedback from the ClinGen Steering Committee and outside experts were incorporated into the recommendations at multiple stages of development. Results: The SVI Working Group developed recommendations for evaluators regarding the assessment of the clinical validity of functional data and a four-step provisional framework to determine the appropriate strength of evidence that can be applied in clinical variant interpretation. These steps are as follows: (1) define the disease mechanism, (2) evaluate the applicability of general classes of assays used in the field, (3) evaluate the validity of specific instances of assays, and (4) apply evidence to individual variant interpretation. We found that a minimum of 11 total pathogenic and benign variant controls are required to reach moderate-level evidence in the absence of rigorous statistical analysis. Conclusions: The recommendations and approach to functional evidence evaluation described here should help clarify the clinical variant interpretation process for functional assays. Further, we hope that these recommendations will help develop productive partnerships with basic scientists who have developed functional assays that are useful for interrogating the function of a variety of genes. [ABSTRACT FROM AUTHOR]

Published
2019
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118. No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing

Author

Easton, Douglas F., Lesueur, Fabienne, Decker, Brennan, Michailidou, Kyriaki, Li, Jun, Allen, Jamie, Luccarini, Craig, Pooley, Karen A., Shah, Mitul, Bolla, Manjeet K., Wang, Qin, Dennis, Joe, Ahmad, Jamil, Thompson, Ella R., Damiola, Francesca, Pertesi, Maroulio, Voegele, Catherine, Mebirouk, Noura, Robinot, Nivonirina, Durand, Geoffroy, Forey, Nathalie, Luben, Robert N., Ahmed, Shahana, Aittomaki, Kristiina, Anton-Culver, Hoda, Arndt, Volker, Baynes, Caroline, Beckman, Matthias W., Benitez, Javier, Van Den Berg, David, Blot, William J., Bogdanova, Natalia V., Bojesen, Stig E., Brenner, Hermann, Chang-Claude, Jenny, Chia, Kee Seng, Choi, Ji-Yeob, Conroy, Don M., Cox, Angela, Cross, Simon S., Czene, Kamila, Darabi, Hatef, Devilee, Peter, Eriksson, Mikael, Fasching, Peter A., Figueroa, Jonine, Flyger, Henrik, Fostira, Florentia, Garcia-Closas, Montserrat, Giles, Graham G., Glendon, Gord, Gonzalez-Neira, Anna, Guenel, Pascal, Haiman, Christopher A., Hall, Per, Hart, Steven N., Hartman, Mikael, Hooning, Maartje J., Hsiung, Chia-Ni, Ito, Hidemi, Jakubowska, Anna, James, Paul A., John, Esther M., Johnson, Nichola, Jones, Michael, Kabisch, Maria, Kang, Daehee, Kosma, Veli-Matti, Kristensen, Vessela, Lambrechts, Diether, Li, Na, Lindblom, Annika, Long, Jirong, Lophatananon, Artitaya, Lubinski, Jan, Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Matsuo, Keitaro, Meindl, Alfons, Mitchell, Gillian, Muir, Kenneth, Nevelsteen, Ines, van den Ouweland, Ans, Peterlongo, Paolo, Phuah, Sze Yee, Pylkas, Katri, Rowley, Simone M., Sangrajrang, Suleeporn, Schmutzler, Rita K., Shen, Chen-Yang, Shu, Xiao-Ou, Southey, Melissa C., Surowy, Harald, Swerdlow, Anthony, Teo, Soo H., Tollenaar, Rob A. E. M., Tomlinson, Ian, Torres, Diana, Truong, Therese, Vachon, Celine, Verhoef, Senno, Wong-Brown, Michelle, Zheng, Wei, Zheng, Ying, Nevanlinna, Heli, Scott, Rodney J., Andrulis, Irene L., Wu, Anna H., Hopper, John L., Couch, Fergus J., Winqvist, Robert, Burwinkel, Barbara, Sawyer, Elinor J., Schmidt, Marjanka K., Rudolph, Anja, Doerk, Thilo, Brauch, Hiltrud, Hamann, Ute, Neuhausen, Susan L., Milne, Roger L., Fletcher, Olivia, Pharoah, Paul D. P., Campbell, Ian G., Dunning, Alison M., Le Calvez-Kelm, Florence, Goldgar, David E., Tavtigian, Sean V., Chenevix-Trench, Georgia, Easton, Douglas F., Lesueur, Fabienne, Decker, Brennan, Michailidou, Kyriaki, Li, Jun, Allen, Jamie, Luccarini, Craig, Pooley, Karen A., Shah, Mitul, Bolla, Manjeet K., Wang, Qin, Dennis, Joe, Ahmad, Jamil, Thompson, Ella R., Damiola, Francesca, Pertesi, Maroulio, Voegele, Catherine, Mebirouk, Noura, Robinot, Nivonirina, Durand, Geoffroy, Forey, Nathalie, Luben, Robert N., Ahmed, Shahana, Aittomaki, Kristiina, Anton-Culver, Hoda, Arndt, Volker, Baynes, Caroline, Beckman, Matthias W., Benitez, Javier, Van Den Berg, David, Blot, William J., Bogdanova, Natalia V., Bojesen, Stig E., Brenner, Hermann, Chang-Claude, Jenny, Chia, Kee Seng, Choi, Ji-Yeob, Conroy, Don M., Cox, Angela, Cross, Simon S., Czene, Kamila, Darabi, Hatef, Devilee, Peter, Eriksson, Mikael, Fasching, Peter A., Figueroa, Jonine, Flyger, Henrik, Fostira, Florentia, Garcia-Closas, Montserrat, Giles, Graham G., Glendon, Gord, Gonzalez-Neira, Anna, Guenel, Pascal, Haiman, Christopher A., Hall, Per, Hart, Steven N., Hartman, Mikael, Hooning, Maartje J., Hsiung, Chia-Ni, Ito, Hidemi, Jakubowska, Anna, James, Paul A., John, Esther M., Johnson, Nichola, Jones, Michael, Kabisch, Maria, Kang, Daehee, Kosma, Veli-Matti, Kristensen, Vessela, Lambrechts, Diether, Li, Na, Lindblom, Annika, Long, Jirong, Lophatananon, Artitaya, Lubinski, Jan, Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Matsuo, Keitaro, Meindl, Alfons, Mitchell, Gillian, Muir, Kenneth, Nevelsteen, Ines, van den Ouweland, Ans, Peterlongo, Paolo, Phuah, Sze Yee, Pylkas, Katri, Rowley, Simone M., Sangrajrang, Suleeporn, Schmutzler, Rita K., Shen, Chen-Yang, Shu, Xiao-Ou, Southey, Melissa C., Surowy, Harald, Swerdlow, Anthony, Teo, Soo H., Tollenaar, Rob A. E. M., Tomlinson, Ian, Torres, Diana, Truong, Therese, Vachon, Celine, Verhoef, Senno, Wong-Brown, Michelle, Zheng, Wei, Zheng, Ying, Nevanlinna, Heli, Scott, Rodney J., Andrulis, Irene L., Wu, Anna H., Hopper, John L., Couch, Fergus J., Winqvist, Robert, Burwinkel, Barbara, Sawyer, Elinor J., Schmidt, Marjanka K., Rudolph, Anja, Doerk, Thilo, Brauch, Hiltrud, Hamann, Ute, Neuhausen, Susan L., Milne, Roger L., Fletcher, Olivia, Pharoah, Paul D. P., Campbell, Ian G., Dunning, Alison M., Le Calvez-Kelm, Florence, Goldgar, David E., Tavtigian, Sean V., and Chenevix-Trench, Georgia

Abstract

Background BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction. Methods We evaluated a truncating variant, p.Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48144 cases and 43607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia. Results The rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75). Conclusions These results suggest that truncating variants in BRIP1, and in particular p.Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels.

Published
2016

119. Resolving the Functional Significance of BRCA1 RING Domain Missense Substitutions

Author

Paquette, Andrew, primary, Tao, Kayoko, additional, Clark, Kathleen A, additional, Stark, Alex W, additional, Rosenthal, Judith, additional, Snow, Angela K, additional, Bell, Russell, additional, Thompson, Bryony A, additional, Unger, Joshua, additional, Milash, Brett A, additional, Pappas, Lisa, additional, Gertz, Jason, additional, Varley, Katherine E, additional, Thomas, Alun, additional, Boucher, Ken, additional, Foulkes, William D, additional, Goldgar, David E, additional, and Tavtigian, Sean V, additional

Published
2016
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121. BRCA1 Circos: A visualisation resource for functional analysis of missense variants

Author

Genetica Sectie Genoomdiagnostiek, Cancer, Jhuraney, Ankita, Velkova, Aneliya, Johnson, Randall C., Kessing, Bailey, Carvalho, Renato S., Whiley, Phillip, Spurdle, Amanda B., Vreeswijk, Maaike P G, Caputo, Sandrine M., Millot, Gael A., Vega, Ana, Coquelle, Nicolas, Galli, Alvaro, Eccles, Diana, Blok, Marinus J., Pal, Tuya, van der Luijt, Rob B., Pena, Marta Santamariña, Neuhausen, Susan L., Donenberg, Talia, Machackova, Eva, Thomas, Simon, Vallée, Maxime, Couch, Fergus J., Tavtigian, Sean V., Glover, J. N Mark, Carvalho, Marcelo A., Brody, Lawrence C., Sharan, Shyam K., Monteiro, Alvaro N., Genetica Sectie Genoomdiagnostiek, Cancer, Jhuraney, Ankita, Velkova, Aneliya, Johnson, Randall C., Kessing, Bailey, Carvalho, Renato S., Whiley, Phillip, Spurdle, Amanda B., Vreeswijk, Maaike P G, Caputo, Sandrine M., Millot, Gael A., Vega, Ana, Coquelle, Nicolas, Galli, Alvaro, Eccles, Diana, Blok, Marinus J., Pal, Tuya, van der Luijt, Rob B., Pena, Marta Santamariña, Neuhausen, Susan L., Donenberg, Talia, Machackova, Eva, Thomas, Simon, Vallée, Maxime, Couch, Fergus J., Tavtigian, Sean V., Glover, J. N Mark, Carvalho, Marcelo A., Brody, Lawrence C., Sharan, Shyam K., and Monteiro, Alvaro N.

Published
2015

122. 447 Effect of COX and EGFR Inhibition on Duodenal Neoplasia in Familial Adenomatous Polyposis: a Randomized Placebo-Controlled Trial

Author

Samadder, N. Jewel, primary, Neklason, Deborah, additional, Kanth, Priyanka, additional, Byrne, Kathryn R., additional, Samowitz, Wade, additional, Jasperson, Kory, additional, Kohlmann, Wendy, additional, Gammon, Amanda, additional, Champine, Marjan, additional, Nathan, Deepika, additional, Boucher, Kenneth M., additional, Greene, Tom, additional, Pappas, Lisa, additional, Fang, John C., additional, Valentine, John F., additional, Hagedorn, Curt, additional, Jones, David, additional, Tavtigian, Sean V., additional, Done, Michelle W., additional, Berry, Therese, additional, Smith, Laurel, additional, Larson, Mikaela, additional, Martineau, Lindsey, additional, Sample, Danielle, additional, Christenson, Cristina, additional, Keener, Megan, additional, Strait, Elena G., additional, Mckinnon, Wendy, additional, Greenblatt, Marc S., additional, Lynch, Patrick M., additional, Burt, Randall W., additional, and Kuwada, Scott K., additional

Published
2015
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123. INHERIT BRCAs Partnering in Oncogenetic Research – The INHERIT BRCAs Experience: Opportunities and Challenges

Author

Avard, Denise, Bridge, Peter, Bucci, Lucie M., Chiquette, Jocelyne, Dorval, Michel, Durocher, Francine, Eston, Doug, Godard, Béatrice, Goldgar, David, Knoppers, Bartha Maria, Laframboise, Rachel, Lespérance, Bernard, Plante, Marie, Tavtigian, Sean V., Vézina, Hélène, Wilson, Brenda, Simard, Jacques, Université de Montréal. Faculté de droit, and Université de Montréal. Faculté de droit. Centre de recherche en droit public

Abstract

[À l'origine dans / Was originally part of : CRDP - Droit, biotechnologie et rapport au milieu]

Published
2005

124. Rare mutations in RINT1 predispose carriers to breast and lynch syndrome-spectrum cancers

Author

Park, Daniel J., Tao, Kayoko, Le Calvez-Kelm, Florence, Nguyen-Dumont, Tu, Robinot, Nivonirina, Hammet, Fleur, Odefrey, Fabrice, Tsimiklis, Helen, Teo, Zhi L., Thingholm, Louise B., Young, Erin L., Voegele, Catherine, Lonie, Andrew, Pope, Bernard J., Roane, Terrell C., Bell, Russell, Hu, Hao, Shankaracharya, Huff, Chad D., Ellis, Jonathan, Li, Jun, Makunin, Igor V., John, Esther M., Andrulis, Irene L., Terry, Mary B., Daly, Mary, Buys, Saundra S., Snyder, Carrie, Lynch, Henry T., Devilee, Peter, Giles, Graham G., Hopper, John L., Feng, Bing Jian, Lesueur, Fabienne, Tavtigian, Sean V., Southey, Melissa C., Goldgar, David E., Park, Daniel J., Tao, Kayoko, Le Calvez-Kelm, Florence, Nguyen-Dumont, Tu, Robinot, Nivonirina, Hammet, Fleur, Odefrey, Fabrice, Tsimiklis, Helen, Teo, Zhi L., Thingholm, Louise B., Young, Erin L., Voegele, Catherine, Lonie, Andrew, Pope, Bernard J., Roane, Terrell C., Bell, Russell, Hu, Hao, Shankaracharya, Huff, Chad D., Ellis, Jonathan, Li, Jun, Makunin, Igor V., John, Esther M., Andrulis, Irene L., Terry, Mary B., Daly, Mary, Buys, Saundra S., Snyder, Carrie, Lynch, Henry T., Devilee, Peter, Giles, Graham G., Hopper, John L., Feng, Bing Jian, Lesueur, Fabienne, Tavtigian, Sean V., Southey, Melissa C., and Goldgar, David E.

Abstract

Approximately half of the familial aggregation of breast cancer remains unexplained. A multiple-case breast cancer family exome-sequencing study identified three likely pathogenic mutations in RINT1 (NM_021930.4) not present in public sequencing databases: RINT1 c.343C>T (p.Q115X), c.1132_1134del (p.M378del), and c.1207G>T (p.D403Y). On the basis of this finding, a population-based case-control mutation-screening study was conducted that identified 29 carriers of rare (minor allele frequency < 0.5%), likely pathogenic variants: 23 in 1,313 early-onset breast cancer cases and six in 1,123 frequency-matched controls [OR, 3.24; 95% confi- dence interval (CI), 1.29-8.17; P = 0.013]. RINT1 mutation screening of probands from 798 multiplecase breast cancer families identified four additional carriers of rare genetic variants. Analysis of the incidence of first primary cancers in families of women carrying RINT1 mutations estimated that carriers were at increased risk of Lynch syndrome-spectrum cancers [standardized incidence ratio (SIR), 3.35; 95% CI, 1.7-6.0; P = 0.005], particularly for relatives diagnosed with cancer under the age of 60 years (SIR, 10.9; 95% CI, 4.7-21; P = 0.0003).

Published
2014

125. A unified test of linkage analysis and rare-variant association for analysis of pedigree sequence data.

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Experimental Neurobiology (Balling Group) [research center], Hu, Hao, Roach, Jared C., Coon, Hilary, Guthery, Stephen L., Voelkerding, Karl V., Margraf, Rebecca L., Durtschi, Jacob D., Tavtigian, Sean V., Shankaracharya, Wu, Wilfred, Scheet, Paul, Wang, Shuoguo, Xing, Jinchuan, Glusman, Gustavo, Hubley, Robert, Li, Hong, Garg, Vidu, Moore, Barry, Hood, Leroy, Galas, David J., Srivastava, Deepak, Reese, Martin G., Jorde, Lynn B., Yandell, Mark, Huff, Chad D., Luxembourg Centre for Systems Biomedicine (LCSB): Experimental Neurobiology (Balling Group) [research center], Hu, Hao, Roach, Jared C., Coon, Hilary, Guthery, Stephen L., Voelkerding, Karl V., Margraf, Rebecca L., Durtschi, Jacob D., Tavtigian, Sean V., Shankaracharya, Wu, Wilfred, Scheet, Paul, Wang, Shuoguo, Xing, Jinchuan, Glusman, Gustavo, Hubley, Robert, Li, Hong, Garg, Vidu, Moore, Barry, Hood, Leroy, Galas, David J., Srivastava, Deepak, Reese, Martin G., Jorde, Lynn B., Yandell, Mark, and Huff, Chad D.

Abstract

High-throughput sequencing of related individuals has become an important tool for studying human disease. However, owing to technical complexity and lack of available tools, most pedigree-based sequencing studies rely on an ad hoc combination of suboptimal analyses. Here we present pedigree-VAAST (pVAAST), a disease-gene identification tool designed for high-throughput sequence data in pedigrees. pVAAST uses a sequence-based model to perform variant and gene-based linkage analysis. Linkage information is then combined with functional prediction and rare variant case-control association information in a unified statistical framework. pVAAST outperformed linkage and rare-variant association tests in simulations and identified disease-causing genes from whole-genome sequence data in three human pedigrees with dominant, recessive and de novo inheritance patterns. The approach is robust to incomplete penetrance and locus heterogeneity and is applicable to a wide variety of genetic traits. pVAAST maintains high power across studies of monogenic, high-penetrance phenotypes in a single pedigree to highly polygenic, common phenotypes involving hundreds of pedigrees.

Published
2014

126. Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database

Author

Thompson, Bryony A, Spurdle, Amanda B, Plazzer, John-Paul, Greenblatt, Marc S, Akagi, Kiwamu, Al-Mulla, Fahd, Bapat, Bharati, Bernstein, Inge, Capellá, Gabriel, den Dunnen, Johan T, du Sart, Desiree, Fabre, Aurelie, Farrell, Michael P, Farrington, Susan M, Frayling, Ian M, Frebourg, Thierry, Goldgar, David E, Heinen, Christopher D, Holinski-Feder, Elke, Kohonen-Corish, Maija, Robinson, Kristina Lagerstedt, Leung, Suet Yi, Martins, Alexandra, Moller, Pal, Morak, Monika, Nystrom, Minna, Peltomaki, Paivi, Pineda, Marta, Qi, Ming, Ramesar, Rajkumar, Rasmussen, Lene Juel, Royer-Pokora, Brigitte, Scott, Rodney J, Sijmons, Rolf, Tavtigian, Sean V, Tops, Carli M, Weber, Thomas, Wijnen, Juul, Woods, Michael O, Macrae, Finlay, Genuardi, Maurizio, Castillejo, Adela, Sexton, Adrienne, Chan, Anthony K W, Viel, Alessandra, Blanco, Amie, French, Amy, Laner, Andreas, Wagner, Anja, van den Ouweland, Ans, Thompson, Bryony A, Spurdle, Amanda B, Plazzer, John-Paul, Greenblatt, Marc S, Akagi, Kiwamu, Al-Mulla, Fahd, Bapat, Bharati, Bernstein, Inge, Capellá, Gabriel, den Dunnen, Johan T, du Sart, Desiree, Fabre, Aurelie, Farrell, Michael P, Farrington, Susan M, Frayling, Ian M, Frebourg, Thierry, Goldgar, David E, Heinen, Christopher D, Holinski-Feder, Elke, Kohonen-Corish, Maija, Robinson, Kristina Lagerstedt, Leung, Suet Yi, Martins, Alexandra, Moller, Pal, Morak, Monika, Nystrom, Minna, Peltomaki, Paivi, Pineda, Marta, Qi, Ming, Ramesar, Rajkumar, Rasmussen, Lene Juel, Royer-Pokora, Brigitte, Scott, Rodney J, Sijmons, Rolf, Tavtigian, Sean V, Tops, Carli M, Weber, Thomas, Wijnen, Juul, Woods, Michael O, Macrae, Finlay, Genuardi, Maurizio, Castillejo, Adela, Sexton, Adrienne, Chan, Anthony K W, Viel, Alessandra, Blanco, Amie, French, Amy, Laner, Andreas, Wagner, Anja, and van den Ouweland, Ans

Abstract

The clinical classification of hereditary sequence variants identified in disease-related genes directly affects clinical management of patients and their relatives. The International Society for Gastrointestinal Hereditary Tumours (InSiGHT) undertook a collaborative effort to develop, test and apply a standardized classification scheme to constitutional variants in the Lynch syndrome-associated genes MLH1, MSH2, MSH6 and PMS2. Unpublished data submission was encouraged to assist in variant classification and was recognized through microattribution. The scheme was refined by multidisciplinary expert committee review of the clinical and functional data available for variants, applied to 2,360 sequence alterations, and disseminated online. Assessment using validated criteria altered classifications for 66% of 12,006 database entries. Clinical recommendations based on transparent evaluation are now possible for 1,370 variants that were not obviously protein truncating from nomenclature. This large-scale endeavor will facilitate the consistent management of families suspected to have Lynch syndrome and demonstrates the value of multidisciplinary collaboration in the curation and classification of variants in public locus-specific databases.

Published
2014

127. Rare key functional domain missense substitutions in MRE11A, RAD50, and NBNcontribute to breast cancer susceptibility: results from a Breast Cancer Family Registry case-control mutation-screening study

Author

Damiola, Francesca, primary, Pertesi, Maroulio, additional, Oliver, Javier, additional, Le Calvez-Kelm, Florence, additional, Voegele, Catherine, additional, Young, Erin L, additional, Robinot, Nivonirina, additional, Forey, Nathalie, additional, Durand, Geoffroy, additional, Vallée, Maxime P, additional, Tao, Kayoko, additional, Roane, Terrell C, additional, Williams, Gareth J, additional, Hopper, John L, additional, Southey, Melissa C, additional, Andrulis, Irene L, additional, John, Esther M, additional, Goldgar, David E, additional, Lesueur, Fabienne, additional, and Tavtigian, Sean V, additional

Published
2014
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129. Haplotype-Based Analysis of Common Variation in the Acetyl-CoA Carboxylase {alpha} Gene and Breast Cancer Risk: A Case-Control Study Nested within the European Prospective Investigation into Cancer and Nutrition.

Author

Sinilnikova, Olga M, McKay, James D, Tavtigian, Sean V, Canzian, Federico, Desilva, Deepika, Biessy, Carine, Monnier, Stéphanie, Dossus, Laure, Boillot, Catherine, Gioia, Lydie, Hughes, David J, Jensen, Majken K, Overvad, Kim, Tjonneland, Anne, Olsen, Anja, Clavel-Chapelon, Francoise, Chajès, Véronique, Joulin, Virginie, Linseisen, Jakob, Chang-Claude, Jenny, Boeing, Heiner, Dahm, Stephan, Trichopoulou, Antonia, Trichopoulos, Dimitrios, Koliva, Maria, Khaw, Kay-Tee, Bingham, Sheila, Allen, Naomi E, Key, Timothy, Palli, Domenico, Panico, Salvatore, Berrino, Franco, Tumino, Rosario, Vineis, Paolo, Bueno-de-Mesquita, H Bas, Peeters, Petra H, van Gils, Carla H, Lund, Eiliv, Pera, Guillem, Quiros, José Ramón, Dorronsoro, Miren, Martinez Garcia, Carmen, Tormo, Maria-José, Ardanaz, Eva, Hallmans, Göran, Lenner, Per, Berglund, Göran, Manjer, Jonas, Riboli, Elio, Lenoir, Gilbert M, Kaaks, Rudolf, Sinilnikova, Olga M, McKay, James D, Tavtigian, Sean V, Canzian, Federico, Desilva, Deepika, Biessy, Carine, Monnier, Stéphanie, Dossus, Laure, Boillot, Catherine, Gioia, Lydie, Hughes, David J, Jensen, Majken K, Overvad, Kim, Tjonneland, Anne, Olsen, Anja, Clavel-Chapelon, Francoise, Chajès, Véronique, Joulin, Virginie, Linseisen, Jakob, Chang-Claude, Jenny, Boeing, Heiner, Dahm, Stephan, Trichopoulou, Antonia, Trichopoulos, Dimitrios, Koliva, Maria, Khaw, Kay-Tee, Bingham, Sheila, Allen, Naomi E, Key, Timothy, Palli, Domenico, Panico, Salvatore, Berrino, Franco, Tumino, Rosario, Vineis, Paolo, Bueno-de-Mesquita, H Bas, Peeters, Petra H, van Gils, Carla H, Lund, Eiliv, Pera, Guillem, Quiros, José Ramón, Dorronsoro, Miren, Martinez Garcia, Carmen, Tormo, Maria-José, Ardanaz, Eva, Hallmans, Göran, Lenner, Per, Berglund, Göran, Manjer, Jonas, Riboli, Elio, Lenoir, Gilbert M, and Kaaks, Rudolf

Published
2007

130. ABRAXAS (FAM175A) and Breast Cancer Susceptibility: No Evidence of Association in the Breast Cancer Family Registry.

Author

Renault, Anne-Laure, Lesueur, Fabienne, Coulombe, Yan, Gobeil, Stéphane, Soucy, Penny, Hamdi, Yosr, Desjardins, Sylvie, Le Calvez-Kelm, Florence, Vallée, Maxime, Voegele, Catherine, null, null, Hopper, John L., Andrulis, Irene L., Southey, Melissa C., John, Esther M., Masson, Jean-Yves, Tavtigian, Sean V., and Simard, Jacques

Subjects
GENETICS of breast cancer, GENETIC mutation, DISEASE susceptibility, DNA damage, DNA repair, MEDICAL registries
Abstract

Approximately half of the familial aggregation of breast cancer remains unexplained. This proportion is less for early-onset disease where familial aggregation is greater, suggesting that other susceptibility genes remain to be discovered. The majority of known breast cancer susceptibility genes are involved in the DNA double-strand break repair pathway. ABRAXAS is involved in this pathway and mutations in this gene impair BRCA1 recruitment to DNA damage foci and increase cell sensitivity to ionizing radiation. Moreover, a recurrent germline mutation was reported in Finnish high-risk breast cancer families. To determine if ABRAXAS could be a breast cancer susceptibility gene in other populations, we conducted a population-based case-control mutation screening study of the coding exons and exon/intron boundaries of ABRAXAS in the Breast Cancer Family Registry. In addition to the common variant p.Asp373Asn, sixteen distinct rare variants were identified. Although no significant difference in allele frequencies between cases and controls was observed for the identified variants, two variants, p.Gly39Val and p.Thr141Ile, were shown to diminish phosphorylation of gamma-H2AX in MCF7 human breast adenocarcinoma cells, an important biomarker of DNA double-strand breaks. Overall, likely damaging or neutral variants were evenly represented among cases and controls suggesting that rare variants in ABRAXAS may explain only a small proportion of hereditary breast cancer. [ABSTRACT FROM AUTHOR]

Published
2016
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131. Evaluation of BRCA1 and BRCA2 mutation prevalence, risk prediction models and a multistep testing approach in French-Canadian families with high risk of breast and ovarian cancer

Author

Simard, Jacques, Dumont, Martine, Moisan, Anne-Marie, Gaborieau, Valérie, Vézina, Hélène, Durocher, Francine, Chiquette, Jocelyne, Plante, Marie, Avard, Denise, Bessette, Paul, Brousseau, Claire, Dorval, Michel, Godard, Béatrice, Houde, Louis, Joly, Yann, Lajoie, Marie-Andrée, Leblanc, Gilles, Lepine, Jean, Lesperance, Bernard, Malouin, Hélène, Parboosingh, Jillian, Pichette, Roxane, Provencher, Louise, Rheaume, Josée, Sinnett, Daniel, Samson, Carolle, Simard, Jean-Claude, Tranchant, Martine, Voyer, Patricia, Easton, Douglas, Tavtigian, Sean V., Knoppers, Bartha-Maria, Laframboise, Rachel, Bridge, Peter, Goldgar, David, Simard, Jacques, Dumont, Martine, Moisan, Anne-Marie, Gaborieau, Valérie, Vézina, Hélène, Durocher, Francine, Chiquette, Jocelyne, Plante, Marie, Avard, Denise, Bessette, Paul, Brousseau, Claire, Dorval, Michel, Godard, Béatrice, Houde, Louis, Joly, Yann, Lajoie, Marie-Andrée, Leblanc, Gilles, Lepine, Jean, Lesperance, Bernard, Malouin, Hélène, Parboosingh, Jillian, Pichette, Roxane, Provencher, Louise, Rheaume, Josée, Sinnett, Daniel, Samson, Carolle, Simard, Jean-Claude, Tranchant, Martine, Voyer, Patricia, Easton, Douglas, Tavtigian, Sean V., Knoppers, Bartha-Maria, Laframboise, Rachel, Bridge, Peter, and Goldgar, David

Abstract

Background and objective: In clinical settings with fixed resources allocated to predictive genetic testing for high-risk cancer predisposition genes, optimal strategies for mutation screening programmes are critically important. These depend on the mutation spectrum found in the population under consideration and the frequency of mutations detected as a function of the personal and family history of cancer, which are both affected by the presence of founder mutations and demographic characteristics of the underlying population. The results of multistep genetic testing for mutations in BRCA1 or BRCA2 in a large series of families with breast cancer in the French-Canadian population of Quebec, Canada are reported. Methods: A total of 256 high-risk families were ascertained from regional familial cancer clinics throughout the province of Quebec. Initially, families were tested for a panel of specific mutations known to occur in this population. Families in which no mutation was identified were then comprehensively tested. Three algorithms to predict the presence of mutations were evaluated, including the prevalence tables provided by Myriad Genetics Laboratories, the Manchester Scoring System and a logistic regression approach based on the data from this study. Results: 8 of the 15 distinct mutations found in 62 BRCA1/BRCA2-positive families had never been previously reported in this population, whereas 82% carried 1 of the 4 mutations currently observed in > or =2 families. In the subset of 191 families in which at least 1 affected individual was tested, 29% carried a mutation. Of these 27 BRCA1-positive and 29 BRCA2-positive families, 48 (86%) were found to harbour a mutation detected by the initial test. Among the remaining 143 inconclusive families, all 8 families found to have a mutation after complete sequencing had Manchester Scores > or =18. The logistic regression and Manchester Scores provided equal predictive power, and both were significantly better than t

Published
2006
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132. FAVR (Filtering and Annotation of Variants that are Rare): methods to facilitate the analysis of rare germline genetic variants from massively parallel sequencing datasets

Author

Pope, Bernard J, primary, Nguyen-Dumont, Tú, additional, Odefrey, Fabrice, additional, Hammet, Fleur, additional, Bell, Russell, additional, Tao, Kayoko, additional, Tavtigian, Sean V, additional, Goldgar, David E, additional, Lonie, Andrew, additional, Southey, Melissa C, additional, and Park, Daniel J, additional

Published
2013
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133. RAD51 and Breast Cancer Susceptibility: No Evidence for Rare Variant Association in the Breast Cancer Family Registry Study

Author

Le Calvez-Kelm, Florence, primary, Oliver, Javier, additional, Damiola, Francesca, additional, Forey, Nathalie, additional, Robinot, Nivonirina, additional, Durand, Geoffroy, additional, Voegele, Catherine, additional, Vallée, Maxime P., additional, Byrnes, Graham, additional, Registry, Breast Cancer Family, additional, Hopper, John L., additional, Southey, Melissa C., additional, Andrulis, Irene L., additional, John, Esther M., additional, Tavtigian, Sean V., additional, and Lesueur, Fabienne, additional

Published
2012
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134. Calibration of Multiple In Silico Tools for Predicting Pathogenicity of Mismatch Repair Gene Missense Substitutions

Author

Thompson, Bryony A., primary, Greenblatt, Marc S., additional, Vallee, Maxime P., additional, Herkert, Johanna C., additional, Tessereau, Chloe, additional, Young, Erin L., additional, Adzhubey, Ivan A., additional, Li, Biao, additional, Bell, Russell, additional, Feng, Bingjian, additional, Mooney, Sean D., additional, Radivojac, Predrag, additional, Sunyaev, Shamil R., additional, Frebourg, Thierry, additional, Hofstra, Robert M.W., additional, Sijmons, Rolf H., additional, Boucher, Ken, additional, Thomas, Alun, additional, Goldgar, David E., additional, Spurdle, Amanda B., additional, and Tavtigian, Sean V., additional

Published
2012
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144. Detailed haplotype analysis at theTP53locus in p.R337H mutation carriers in the population of Southern Brazil: evidence for a founder effect

Author

Garritano, Sonia, primary, Gemignani, Federica, additional, Palmero, Edenir Inez, additional, Olivier, Magali, additional, Martel-Planche, Ghyslaine, additional, Le Calvez-Kelm, Florence, additional, Brugiéres, Laurence, additional, Vargas, Fernando Regla, additional, Brentani, Ricardo Renzo, additional, Ashton-Prolla, Patricia, additional, Landi, Stefano, additional, Tavtigian, Sean V., additional, Hainaut, Pierre, additional, and Achatz, Maria Isabel W., additional

Published
2010
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146. ClassifyingMLH1andMSH2variants using bioinformatic prediction, splicing assays, segregation, and tumor characteristics

Author

Arnold, Sven, primary, Buchanan, Daniel D., additional, Barker, Melissa, additional, Jaskowski, Lesley, additional, Walsh, Michael D., additional, Birney, Genevieve, additional, Woods, Michael O., additional, Hopper, John L., additional, Jenkins, Mark A., additional, Brown, Melissa A., additional, Tavtigian, Sean V., additional, Goldgar, David E., additional, Young, Joanne P., additional, and Spurdle, Amanda B., additional

Published
2009
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148. Functional Assays for Classification of BRCA2 Variants of Uncertain Significance

Author

Farrugia, Daniel J., primary, Agarwal, Mukesh K., additional, Pankratz, Vernon S., additional, Deffenbaugh, Amie M., additional, Pruss, Dmitry, additional, Frye, Cynthia, additional, Wadum, Linda, additional, Johnson, Kiley, additional, Mentlick, Jennifer, additional, Tavtigian, Sean V., additional, Goldgar, David E., additional, and Couch, Fergus J., additional

Published
2008
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149. Clinical Classification of BRCA1 and BRCA2 DNA Sequence Variants: The Value of Cytokeratin Profiles and Evolutionary Analysis—A Report From the kConFab Investigators

Author

Spurdle, Amanda B., primary, Lakhani, Sunil R., additional, Healey, Sue, additional, Parry, Suzanne, additional, Da Silva, Leonard M., additional, Brinkworth, Ross, additional, Hopper, John L., additional, Brown, Melissa A., additional, Babikyan, Davit, additional, Chenevix-Trench, Georgia, additional, Tavtigian, Sean V., additional, and Goldgar, David E., additional

Published
2008
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150. Identification of BRCA1 missense substitutions that confer partial functional activity: potential moderate risk variants?

Author

Lovelock, Paul K, primary, Spurdle, Amanda B, additional, Mok, Myth TS, additional, Farrugia, Daniel J, additional, Lakhani, Sunil R, additional, Healey, Sue, additional, Arnold, Stephen, additional, Buchanan, Daniel, additional, Investigators, kConFab, additional, Couch, Fergus J, additional, Henderson, Beric R, additional, Goldgar, David E, additional, Tavtigian, Sean V, additional, Chenevix-Trench, Georgia, additional, and Brown, Melissa A, additional

Published
2007
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