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1. Evidence-based recommendations for gene-specific ACMG/AMP variant classification from the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel

Author

Parsons, Michael T, de la Hoya, Miguel, Richardson, Marcy E, Tudini, Emma, Anderson, Michael, Berkofsky-Fessler, Windy, Caputo, Sandrine M, Chan, Raymond C, Cline, Melissa S, Feng, Bing-Jian, Fortuno, Cristina, Gomez-Garcia, Encarna, Hadler, Johanna, Hiraki, Susan, Holdren, Megan, Houdayer, Claude, Hruska, Kathleen, James, Paul, Karam, Rachid, Leong, Huei San, Martins, Alexandra, Mensenkamp, Arjen R, Monteiro, Alvaro N, Nathan, Vaishnavi, O'Connor, Robert, Pedersen, Inge Sokilde, Pesaran, Tina, Radice, Paolo, Schmidt, Gunnar, Southey, Melissa, Tavtigian, Sean, Thompson, Bryony A, Toland, Amanda E, Turnbull, Clare, Vogel, Maartje J, Weyandt, Jamie, Wiggins, George AR, Zec, Lauren, Couch, Fergus J, Walker, Logan C, Vreeswijk, Maaike PG, Goldgar, David E, and Spurdle, Amanda B

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Women's Health, Breast Cancer, Ovarian Cancer, Cancer, Rare Diseases, Good Health and Well Being, ACMG/AMP variant curation guidelines, BRCA1, BRCA2, ClinGen, ClinVar, VCEP, Humans, BRCA2 Protein, BRCA1 Protein, Female, Genetic Variation, Breast Neoplasms, Genomics, Databases, Genetic, Ovarian Neoplasms, Genetic Predisposition to Disease, Genetic Testing, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

The ENIGMA research consortium develops and applies methods to determine clinical significance of variants in hereditary breast and ovarian cancer genes. An ENIGMA BRCA1/2 classification sub-group, formed in 2015 as a ClinGen external expert panel, evolved into a ClinGen internal Variant Curation Expert Panel (VCEP) to align with Food and Drug Administration recognized processes for ClinVar contributions. The VCEP reviewed American College of Medical Genetics and Genomics/Association of Molecular Pathology (ACMG/AMP) classification criteria for relevance to interpreting BRCA1 and BRCA2 variants. Statistical methods were used to calibrate evidence strength for different data types. Pilot specifications were tested on 40 variants and documentation revised for clarity and ease of use. The original criterion descriptions for 13 evidence codes were considered non-applicable or overlapping with other criteria. Scenario of use was extended or re-purposed for eight codes. Extensive analysis and/or data review informed specification descriptions and weights for all codes. Specifications were applied to pilot variants with pre-existing ClinVar classification as follows: 13 uncertain significance or conflicting, 14 pathogenic and/or likely pathogenic, and 13 benign and/or likely benign. Review resolved classification for 11/13 uncertain significance or conflicting variants and retained or improved confidence in classification for the remaining variants. Alignment of pre-existing ENIGMA research classification processes with ACMG/AMP classification guidelines highlighted several gaps in the research processes and the baseline ACMG/AMP criteria. Calibration of evidence strength was key to justify utility and strength of different data types for gene-specific application. The gene-specific criteria demonstrated value for improving ACMG/AMP-aligned classification of BRCA1 and BRCA2 variants.

Published
2024

2. A Likelihood Ratio Approach for Utilizing Case‐Control Data in the Clinical Classification of Rare Sequence Variants: Application to BRCA1 and BRCA2

Author

Zanti, Maria, O′Mahony, Denise G, Parsons, Michael T, Li, Hongyan, Dennis, Joe, Aittomäkkiki, Kristiina, Andrulis, Irene L, Anton-Culver, Hoda, Aronson, Kristan J, Augustinsson, Annelie, Becher, Heiko, Bojesen, Stig E, Bolla, Manjeet K, Brenner, Hermann, Brown, Melissa A, Buys, Saundra S, Canzian, Federico, Caputo, Sandrine M, Castelao, Jose E, Chang-Claude, Jenny, Collaborators, GC-HBOC study, Czene, Kamila, Daly, Mary B, De Nicolo, Arcangela, Devilee, Peter, Dörk, Thilo, Dunning, Alison M, Dwek, Miriam, Eccles, Diana M, Engel, Christoph, Evans, D Gareth, Fasching, Peter A, Gago-Dominguez, Manuela, García-Closas, Montserrat, García-Sáenz, José A, Gentry-Maharaj, Aleksandra, Giele, Willemina RR Geurts-, Giles, Graham G, Glendon, Gord, Goldberg, Mark S, Garcia, Encarna B Gómez, Güendert, Melanie, Guénel, Pascal, Hahnen, Eric, Haiman, Christopher A, Hall, Per, Hamann, Ute, Harkness, Elaine F, Hogervorst, Frans BL, Hollestelle, Antoinette, Hoppe, Reiner, Hopper, John L, Houdayer, Claude, Houlston, Richard S, Howell, Anthony, Investigators, ABCTB, Jakimovska, Milena, Jakubowska, Anna, Jernström, Helena, John, Esther M, Kaaks, Rudolf, Kitahara, Cari M, Koutros, Stella, Kraft, Peter, Kristensen, Vessela N, Lacey, James V, Lambrechts, Diether, Léoné, Melanie, Lindblom, Annika, Lubiński, Jan, Lush, Michael, Mannermaa, Arto, Manoochehri, Mehdi, Manoukian, Siranoush, Margolin, Sara, Martinez, Maria Elena, Menon, Usha, Milne, Roger L, Monteiro, Alvaro N, Murphy, Rachel A, Neuhausen, Susan L, Nevanlinna, Heli, Newman, William G, Offit, Kenneth, Park, Sue K, James, Paul, Peterlongo, Paolo, Peto, Julian, Plaseska-Karanfilska, Dijana, Punie, Kevin, Radice, Paolo, Rashid, Muhammad U, Rennert, Gad, Romero, Atocha, Rosenberg, Efraim H, Saloustros, Emmanouil, Sandler, Dale P, Schmidt, Marjanka K, Schmutzler, Rita K, and Shu, Xiao-Ou

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Biotechnology, Genetic Testing, Prevention, Cancer, Human Genome, Women's Health, Breast Cancer, 2.1 Biological and endogenous factors, Good Health and Well Being, Humans, Case-Control Studies, BRCA2 Protein, Genetic Predisposition to Disease, Female, BRCA1 Protein, Breast Neoplasms, Likelihood Functions, Genetic Variation, Penetrance, GC-HBOC study Collaborators, ABCTB Investigators, ACMG/AMP, BRCA, PS4, VUS, case-control, likelihood ratio, variant classification, Clinical Sciences, Genetics & Heredity, Clinical sciences
Abstract

A large number of variants identified through clinical genetic testing in disease susceptibility genes, are of uncertain significance (VUS). Following the recommendations of the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP), the frequency in case-control datasets (PS4 criterion), can inform their interpretation. We present a novel case-control likelihood ratio-based method that incorporates gene-specific age-related penetrance. We demonstrate the utility of this method in the analysis of simulated and real datasets. In the analyses of simulated data, the likelihood ratio method was more powerful compared to other methods. Likelihood ratios were calculated for a case-control dataset of BRCA1 and BRCA2 variants from the Breast Cancer Association Consortium (BCAC), and compared with logistic regression results. A larger number of variants reached evidence in favor of pathogenicity, and a substantial number of variants had evidence against pathogenicity - findings that would not have been reached using other case-control analysis methods. Our novel method provides greater power to classify rare variants compared to classical case-control methods. As an initiative from the ENIGMA Analytical Working Group, we provide user-friendly scripts and pre-formatted excel calculators for implementation of the method for rare variants in BRCA1, BRCA2 and other high-risk genes with known penetrance.

Published
2023

3. Cancer Risks Associated With BRCA1 and BRCA2 Pathogenic Variants

Author

Li, Shuai, Silvestri, Valentina, Leslie, Goska, Rebbeck, Timothy R, Neuhausen, Susan L, Hopper, John L, Nielsen, Henriette Roed, Lee, Andrew, Yang, Xin, McGuffog, Lesley, Parsons, Michael T, Andrulis, Irene L, Arnold, Norbert, Belotti, Muriel, Borg, Åke, Buecher, Bruno, Buys, Saundra S, Caputo, Sandrine M, Chung, Wendy K, Colas, Chrystelle, Colonna, Sarah V, Cook, Jackie, Daly, Mary B, de la Hoya, Miguel, de Pauw, Antoine, Delhomelle, Hélène, Eason, Jacqueline, Engel, Christoph, Evans, D Gareth, Faust, Ulrike, Fehm, Tanja N, Fostira, Florentia, Fountzilas, George, Frone, Megan, Garcia-Barberan, Vanesa, Garre, Pilar, Gauthier-Villars, Marion, Gehrig, Andrea, Glendon, Gord, Goldgar, David E, Golmard, Lisa, Greene, Mark H, Hahnen, Eric, Hamann, Ute, Hanson, Helen, Hassan, Tiara, Hentschel, Julia, Horvath, Judit, Izatt, Louise, Janavicius, Ramunas, Jiao, Yue, John, Esther M, Karlan, Beth Y, Kim, Sung-Won, Konstantopoulou, Irene, Kwong, Ava, Laugé, Anthony, Lee, Jong Won, Lesueur, Fabienne, Mebirouk, Noura, Meindl, Alfons, Mouret-Fourme, Emmanuelle, Musgrave, Hannah, Yie, Joanne Ngeow Yuen, Niederacher, Dieter, Park, Sue K, Pedersen, Inge Sokilde, Ramser, Juliane, Ramus, Susan J, Rantala, Johanna, Rashid, Muhammad U, Reichl, Florian, Ritter, Julia, Rump, Andreas, Santamariña, Marta, Saule, Claire, Schmidt, Gunnar, Schmutzler, Rita K, Senter, Leigha, Shariff, Saba, Singer, Christian F, Southey, Melissa C, Stoppa-Lyonnet, Dominique, Sutter, Christian, Tan, Yen, Teo, Soo Hwang, Terry, Mary Beth, Thomassen, Mads, Tischkowitz, Marc, Toland, Amanda E, Torres, Diana, Vega, Ana, Wagner, Sebastian A, Wang-Gohrke, Shan, Wappenschmidt, Barbara, Weber, Bernhard HF, Yannoukakos, Drakoulis, Spurdle, Amanda B, Easton, Douglas F, and Chenevix-Trench, Georgia

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Prostate Cancer, Women's Health, Digestive Diseases, Breast Cancer, Ovarian Cancer, Pancreatic Cancer, Prevention, Cancer, Urologic Diseases, Rare Diseases, 2.1 Biological and endogenous factors, BRCA1 Protein, BRCA2 Protein, Breast Neoplasms, Breast Neoplasms, Male, Female, Genetic Predisposition to Disease, Heterozygote, Humans, Infant, Newborn, Male, Mutation, Ovarian Neoplasms, Pancreatic Neoplasms, Risk, Clinical Sciences, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

PurposeTo provide precise age-specific risk estimates of cancers other than female breast and ovarian cancers associated with pathogenic variants (PVs) in BRCA1 and BRCA2 for effective cancer risk management.MethodsWe used data from 3,184 BRCA1 and 2,157 BRCA2 families in the Consortium of Investigators of Modifiers of BRCA1/2 to estimate age-specific relative (RR) and absolute risks for 22 first primary cancer types adjusting for family ascertainment.ResultsBRCA1 PVs were associated with risks of male breast (RR = 4.30; 95% CI, 1.09 to 16.96), pancreatic (RR = 2.36; 95% CI, 1.51 to 3.68), and stomach (RR = 2.17; 95% CI, 1.25 to 3.77) cancers. Associations with colorectal and gallbladder cancers were also suggested. BRCA2 PVs were associated with risks of male breast (RR = 44.0; 95% CI, 21.3 to 90.9), stomach (RR = 3.69; 95% CI, 2.40 to 5.67), pancreatic (RR = 3.34; 95% CI, 2.21 to 5.06), and prostate (RR = 2.22; 95% CI, 1.63 to 3.03) cancers. The stomach cancer RR was higher for females than males (6.89 v 2.76; P = .04). The absolute risks to age 80 years ranged from 0.4% for male breast cancer to approximately 2.5% for pancreatic cancer for BRCA1 carriers and from approximately 2.5% for pancreatic cancer to 27% for prostate cancer for BRCA2 carriers.ConclusionIn addition to female breast and ovarian cancers, BRCA1 and BRCA2 PVs are associated with increased risks of male breast, pancreatic, stomach, and prostate (only BRCA2 PVs) cancers, but not with the risks of other previously suggested cancers. The estimated age-specific risks will refine cancer risk management in men and women with BRCA1/2 PVs.

Published
2022

5. Association and performance of polygenic risk scores for breast cancer among French women presenting or not a familial predisposition to the disease

Author

Jiao, Yue, Truong, Thérèse, Eon-Marchais, Séverine, Mebirouk, Noura, Caputo, Sandrine M., Dondon, Marie-Gabrielle, Karimi, Mojgan, Le Gal, Dorothée, Beauvallet, Juana, Le Floch, Édith, Dandine-Roulland, Claire, Bacq-Daian, Delphine, Olaso, Robert, Albuisson, Juliette, Audebert-Bellanger, Séverine, Berthet, Pascaline, Bonadona, Valérie, Buecher, Bruno, Caron, Olivier, Cavaillé, Mathias, Chiesa, Jean, Colas, Chrystelle, Collonge-Rame, Marie-Agnès, Coupier, Isabelle, Delnatte, Capucine, De Pauw, Antoine, Dreyfus, Hélène, Fert-Ferrer, Sandra, Gauthier-Villars, Marion, Gesta, Paul, Giraud, Sophie, Gladieff, Laurence, Golmard, Lisa, Lasset, Christine, Lejeune-Dumoulin, Sophie, Léoné, Mélanie, Limacher, Jean-Marc, Lortholary, Alain, Luporsi, Élisabeth, Mari, Véronique, Maugard, Christine M., Mortemousque, Isabelle, Mouret-Fourme, Emmanuelle, Nambot, Sophie, Noguès, Catherine, Popovici, Cornel, Prieur, Fabienne, Pujol, Pascal, Sevenet, Nicolas, Sobol, Hagay, Toulas, Christine, Uhrhammer, Nancy, Vaur, Dominique, Venat, Laurence, Boland-Augé, Anne, Guénel, Pascal, Deleuze, Jean-François, Stoppa-Lyonnet, Dominique, Andrieu, Nadine, and Lesueur, Fabienne

Published
2023
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6. Height and Body Mass Index as Modifiers of Breast Cancer Risk in BRCA1/2 Mutation Carriers: A Mendelian Randomization Study.

Author

Qian, Frank, Wang, Shengfeng, Mitchell, Jonathan, McGuffog, Lesley, Barrowdale, Daniel, Leslie, Goska, Oosterwijk, Jan C, Chung, Wendy K, Evans, D Gareth, Engel, Christoph, Kast, Karin, Aalfs, Cora M, Adank, Muriel A, Adlard, Julian, Agnarsson, Bjarni A, Aittomäki, Kristiina, Alducci, Elisa, Andrulis, Irene L, Arun, Banu K, Ausems, Margreet GEM, Azzollini, Jacopo, Barouk-Simonet, Emmanuelle, Barwell, Julian, Belotti, Muriel, Benitez, Javier, Berger, Andreas, Borg, Ake, Bradbury, Angela R, Brunet, Joan, Buys, Saundra S, Caldes, Trinidad, Caligo, Maria A, Campbell, Ian, Caputo, Sandrine M, Chiquette, Jocelyne, Claes, Kathleen BM, Margriet Collée, J, Couch, Fergus J, Coupier, Isabelle, Daly, Mary B, Davidson, Rosemarie, Diez, Orland, Domchek, Susan M, Donaldson, Alan, Dorfling, Cecilia M, Eeles, Ros, Feliubadaló, Lidia, Foretova, Lenka, Fowler, Jeffrey, Friedman, Eitan, Frost, Debra, Ganz, Patricia A, Garber, Judy, Garcia-Barberan, Vanesa, Glendon, Gord, Godwin, Andrew K, Gómez Garcia, Encarna B, Gronwald, Jacek, Hahnen, Eric, Hamann, Ute, Henderson, Alex, Hendricks, Carolyn B, Hopper, John L, Hulick, Peter J, Imyanitov, Evgeny N, Isaacs, Claudine, Izatt, Louise, Izquierdo, Ángel, Jakubowska, Anna, Kaczmarek, Katarzyna, Kang, Eunyoung, Karlan, Beth Y, Kets, Carolien M, Kim, Sung-Won, Kim, Zisun, Kwong, Ava, Laitman, Yael, Lasset, Christine, Hyuk Lee, Min, Won Lee, Jong, Lee, Jihyoun, Lester, Jenny, Lesueur, Fabienne, Loud, Jennifer T, Lubinski, Jan, Mebirouk, Noura, Meijers-Heijboer, Hanne EJ, Meindl, Alfons, Miller, Austin, Montagna, Marco, Mooij, Thea M, Morrison, Patrick J, Mouret-Fourme, Emmanuelle, Nathanson, Katherine L, Neuhausen, Susan L, Nevanlinna, Heli, Niederacher, Dieter, Nielsen, Finn C, Nussbaum, Robert L, and Offit, Kenneth

Subjects
GEMO Study Collaborators, HEBON, EMBRACE, Humans, Breast Neoplasms, Genetic Predisposition to Disease, BRCA1 Protein, BRCA2 Protein, Body Mass Index, Body Height, Prognosis, Risk Factors, Mutation, Polymorphism, Single Nucleotide, Adult, Female, Mendelian Randomization Analysis, Oncology & Carcinogenesis, Oncology and Carcinogenesis
Abstract

BackgroundBRCA1/2 mutations confer high lifetime risk of breast cancer, although other factors may modify this risk. Whether height or body mass index (BMI) modifies breast cancer risk in BRCA1/2 mutation carriers remains unclear.MethodsWe used Mendelian randomization approaches to evaluate the association of height and BMI on breast cancer risk, using data from the Consortium of Investigators of Modifiers of BRCA1/2 with 14 676 BRCA1 and 7912 BRCA2 mutation carriers, including 11 451 cases of breast cancer. We created a height genetic score using 586 height-associated variants and a BMI genetic score using 93 BMI-associated variants. We examined both observed and genetically determined height and BMI with breast cancer risk using weighted Cox models. All statistical tests were two-sided.ResultsObserved height was positively associated with breast cancer risk (HR = 1.09 per 10 cm increase, 95% confidence interval [CI] = 1.0 to 1.17; P = 1.17). Height genetic score was positively associated with breast cancer, although this was not statistically significant (per 10 cm increase in genetically predicted height, HR = 1.04, 95% CI = 0.93 to 1.17; P = .47). Observed BMI was inversely associated with breast cancer risk (per 5 kg/m2 increase, HR = 0.94, 95% CI = 0.90 to 0.98; P = .007). BMI genetic score was also inversely associated with breast cancer risk (per 5 kg/m2 increase in genetically predicted BMI, HR = 0.87, 95% CI = 0.76 to 0.98; P = .02). BMI was primarily associated with premenopausal breast cancer.ConclusionHeight is associated with overall breast cancer and BMI is associated with premenopausal breast cancer in BRCA1/2 mutation carriers. Incorporating height and BMI, particularly genetic score, into risk assessment may improve cancer management.

Published
2019

7. Value of the loss of heterozygosity to BRCA1 variant classification

Author

Santana dos Santos, Elizabeth, Spurdle, Amanda B., Carraro, Dirce M., Briaux, Adrien, Southey, Melissa, Torrezan, Giovana, Petitalot, Ambre, Leman, Raphael, Lafitte, Philippe, Meseure, Didier, Driouch, Keltouma, Side, Lucy, Brewer, Carole, Beck, Sarah, Melville, Athalie, Callaway, Alison, Revillion, Françoise, Folgueira, Maria A. A. Koike, Parsons, Michael T., Thorne, Heather, Vincent-Salomon, Anne, Stoppa-Lyonnet, Dominique, Bieche, Ivan, Caputo, Sandrine M., and Rouleau, Etienne

Published
2022
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8. Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations.

Author

Rebbeck, Timothy R, Friebel, Tara M, Friedman, Eitan, Hamann, Ute, Huo, Dezheng, Kwong, Ava, Olah, Edith, Olopade, Olufunmilayo I, Solano, Angela R, Teo, Soo-Hwang, Thomassen, Mads, Weitzel, Jeffrey N, Chan, TL, Couch, Fergus J, Goldgar, David E, Kruse, Torben A, Palmero, Edenir Inêz, Park, Sue Kyung, Torres, Diana, van Rensburg, Elizabeth J, McGuffog, Lesley, Parsons, Michael T, Leslie, Goska, Aalfs, Cora M, Abugattas, Julio, Adlard, Julian, Agata, Simona, Aittomäki, Kristiina, Andrews, Lesley, Andrulis, Irene L, Arason, Adalgeir, Arnold, Norbert, Arun, Banu K, Asseryanis, Ella, Auerbach, Leo, Azzollini, Jacopo, Balmaña, Judith, Barile, Monica, Barkardottir, Rosa B, Barrowdale, Daniel, Benitez, Javier, Berger, Andreas, Berger, Raanan, Blanco, Amie M, Blazer, Kathleen R, Blok, Marinus J, Bonadona, Valérie, Bonanni, Bernardo, Bradbury, Angela R, Brewer, Carole, Buecher, Bruno, Buys, Saundra S, Caldes, Trinidad, Caliebe, Almuth, Caligo, Maria A, Campbell, Ian, Caputo, Sandrine M, Chiquette, Jocelyne, Chung, Wendy K, Claes, Kathleen BM, Collée, J Margriet, Cook, Jackie, Davidson, Rosemarie, de la Hoya, Miguel, De Leeneer, Kim, de Pauw, Antoine, Delnatte, Capucine, Diez, Orland, Ding, Yuan Chun, Ditsch, Nina, Domchek, Susan M, Dorfling, Cecilia M, Velazquez, Carolina, Dworniczak, Bernd, Eason, Jacqueline, Easton, Douglas F, Eeles, Ros, Ehrencrona, Hans, Ejlertsen, Bent, EMBRACE, Engel, Christoph, Engert, Stefanie, Evans, D Gareth, Faivre, Laurence, Feliubadaló, Lidia, Ferrer, Sandra Fert, Foretova, Lenka, Fowler, Jeffrey, Frost, Debra, Galvão, Henrique CR, Ganz, Patricia A, Garber, Judy, Gauthier-Villars, Marion, Gehrig, Andrea, GEMO Study Collaborators, Gerdes, Anne-Marie, Gesta, Paul, Giannini, Giuseppe, Giraud, Sophie, and Glendon, Gord

Subjects
EMBRACE, GEMO Study Collaborators, HEBON, Humans, BRCA1 Protein, BRCA2 Protein, Family, Mutation, Geography, Internationality, Databases, Genetic, BRCA1, BRCA2, breast cancer, ethnicity, geography, mutation, ovarian cancer, Databases, Genetic, Genetics & Heredity, Genetics, Clinical Sciences
Abstract

The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations.

Published
2018

9. The BRCA2 R2645G variant increases DNA binding and induces hyper-recombination

Author

Alvaro-Aranda, Lucia, primary, Petitalot, Ambre, additional, Djeghmoum, Yasmina, additional, Panigada, Davide, additional, Singh, Jenny Kaur, additional, Ehlén, Åsa, additional, Vugic, Domagoj, additional, Martin, Charlotte, additional, Miron, Simona, additional, Contreras-Perez, Aida, additional, Nhiri, Naima, additional, Boucherit, Virginie, additional, Lafitte, Philippe, additional, Dumoulin, Isaac, additional, Rouleau, Etienne, additional, Jacquet, Eric, additional, Feliubadaló, Lidia, additional, del Valle, Jesús, additional, Stoppa-Lyonnet, Dominique, additional, Zinn-Justin, Sophie, additional, Lázaro, Conxi, additional, Caputo, Sandrine M, additional, and Carreira, Aura, additional

Published
2023
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10. Male breast cancer: No evidence for mosaic BRCA1 promoter methylation involvement

Author

Schwartz, Mathias, primary, Ibadioune, Sabrina, additional, Vacher, Sophie, additional, Villy, Marie-Charlotte, additional, Trabelsi-Grati, Olfa, additional, Le Gall, Jessica, additional, Caputo, Sandrine M., additional, Delhomelle, Hélène, additional, Warcoin, Mathilde, additional, Moncoutier, Virginie, additional, Bourneix, Christine, additional, Boutry-Kryza, Nadia, additional, De Pauw, Antoine, additional, Stern, Marc-Henri, additional, Buecher, Bruno, additional, Mouret-Fourme, Emmanuelle, additional, Colas, Chrystelle, additional, Stoppa-Lyonnet, Dominique, additional, Masliah-Planchon, Julien, additional, Golmard, Lisa, additional, and Bieche, Ivan, additional

Published
2023
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11. A new hybrid record linkage process to make epidemiological databases interoperable: application to the GEMO and GENEPSO studies involving BRCA1 and BRCA2 mutation carriers

Author

Jiao, Yue, Lesueur, Fabienne, Azencott, Chloé-Agathe, Laurent, Maïté, Mebirouk, Noura, Laborde, Lilian, Beauvallet, Juana, Dondon, Marie-Gabrielle, Eon-Marchais, Séverine, Laugé, Anthony, Noguès, Catherine, Andrieu, Nadine, Stoppa-Lyonnet, Dominique, and Caputo, Sandrine M.

Published
2021
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13. Mosaic BRCA1 promoter methylation contribution in hereditary breast/ovarian cancer pedigrees.

Author

Schwartz, Mathias, Ibadioune, Sabrina, Chansavang, Albain, Vacher, Sophie, Caputo, Sandrine M., Delhomelle, Hélène, Wong, Jennifer, Abidallah, Khadija, Moncoutier, Virginie, Becette, Véronique, Popova, Tatiana, Suybeng, Voreak, De Pauw, Antoine, Stern, Marc-Henri, Colas, Chrystelle, Mouret-Fourme, Emmanuelle, Stoppa-Lyonnet, Dominique, Golmard, Lisa, Bieche, Ivan, and Masliah-Planchon, Julien

Abstract

Purpose Mosaic BRCA1 promoter methylation (BRCA1meth) increases the risk of early-onset breast cancer, triple-negative breast cancer and ovarian cancer. As mosaic BRCA1meth are believed to occur de novo, their role in family breast/ovarian cancer has not been assessed. Patients Blood-derived DNA from 20 unrelated affected cases from families with aggregation of breast/ovarian cancer, but with no germline pathogenic variants in BRCA1/2, PALB2 or RAD51C/D, were screened by methylation-sensitive high-resolution melting. CpG analysis was performed by pyrosequencing on blood and buccal swab. Two probands carried a pathogenic variant in a moderate-penetrance gene (ATM and BARD1), and 8 of 18 others (44%) carried BRCA1meth (vs none of the 20 age-matched controls). Involvement of BRCA1 in tumourigenesis in methylated probands was demonstrated in most tested cases by detection of a loss of heterozygosity and a homologous recombination deficiency signature. Among the eight methylated probands, two had relatives with breast cancer with detectable BRCA1meth in blood, including one with high methylation levels in two non-tumour tissues. Conclusions The high prevalence of mosaic BRCA1meth in patients with breast/ovarian cancer with affected relatives, as well as this first description of a family aggregation of mosaic BRCA1meth, shows how this de novo event can contribute to hereditary breast/ovarian cancer pedigrees. [ABSTRACT FROM AUTHOR]

Published
2024
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14. GermlineHPF1retrogene insertion inRB1gene involved in cancer predisposition

Author

Le Gall, Jessica, primary, Dehainault, Catherine, additional, Boutte, Matteo, additional, Petitalot, Ambre, additional, Caputo, Sandrine M, additional, Courtois, Laura, additional, Vacher, Sophie, additional, Bieche, Ivan, additional, Radvanyi, François, additional, Pacquement, Hélène, additional, Doz, François, additional, Lumbroso-Le Rouic, Livia, additional, Gauthier Villars, Marion, additional, Stoppa-Lyonnet, Dominique, additional, Lallemand, François, additional, Houdayer, Claude, additional, and Golmard, Lisa, additional

Published
2023
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15. Combined Tumor-Based BRCA1/2 and TP53 Mutation Testing in Ovarian Cancer

Author

Borcoman, Edith, primary, Santana dos Santos, Elizabeth, additional, Genestie, Catherine, additional, Pautier, Patricia, additional, Lacroix, Ludovic, additional, Caputo, Sandrine M., additional, Cabaret, Odile, additional, Guillaud-Bataille, Marine, additional, Michels, Judith, additional, Auguste, Aurelie, additional, Leary, Alexandra, additional, and Rouleau, Etienne, additional

Published
2023
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17. Germline HPF1 retrogene insertion in RB1 gene involved in cancer predisposition.

Author

Le Gall, Jessica, Dehainault, Catherine, Boutte, Matteo, Petitalot, Ambre, Caputo, Sandrine M., Courtois, Laura, Vacher, Sophie, Bieche, Ivan, Radvanyi, François, Pacquement, Hélène, Doz, François, Rouic, Livia Lumbroso-Le, Villars, Marion Gauthier, Stoppa-Lyonnet, Dominique, Lallemand, François, Houdayer, Claude, and Golmard, Lisa

Abstract

About half of the human genome is composed of repeated sequences derived from mobile elements, mainly retrotransposons, generally without pathogenic effect. Familial forms of retinoblastoma are caused by germline pathogenic variants in RB1 gene. Here, we describe a family with retinoblastoma affecting a father and his son. No pathogenic variant was identified after DNA analysis of RB1 gene coding sequence and exonintron junctions. However, RB1 mRNA analysis showed a chimeric transcript with insertion of 114 nucleotides from HPF1 gene inside RB1 gene. This chimeric transcript led to an insertion of 38 amino acids in functional domain of retinoblastoma protein. Subsequent DNA analysis in RB1 intron 17 revealed the presence of a full-length HPF1 retrogene insertion in opposite orientation. Functional assay shows that this insertion has a deleterious impact on retinoblastoma protein function. This is the first report of a full-length retrogene insertion involved in human Mendelian disease leading to a chimeric transcript and a non-functional chimeric protein. Some retrogene insertions may be missed by standard diagnostic genetic testing, so contribution of retrogene insertions to human disease may be underestimated. The increasing use of whole genome sequencing in diagnostic settings will help to get a more comprehensive view of retrogenes. [ABSTRACT FROM AUTHOR]

Published
2024
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18. Male breast cancer: No evidence for mosaic BRCA1 promoter methylation involvement

Author

Schwartz, Mathias, Ibadioune, Sabrina, Vacher, Sophie, Villy, Marie-Charlotte, Trabelsi-Grati, Olfa, Le Gall, Jessica, Caputo, Sandrine M., Delhomelle, Hélène, Warcoin, Mathilde, Moncoutier, Virginie, Bourneix, Christine, Boutry-Kryza, Nadia, De Pauw, Antoine, Stern, Marc-Henri, Buecher, Bruno, Mouret-Fourme, Emmanuelle, Colas, Chrystelle, Stoppa-Lyonnet, Dominique, Masliah-Planchon, Julien, Golmard, Lisa, and Bieche, Ivan

Published
2024
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19. Adaptive nanopore sequencing to determine pathogenicity of BRCA1 exonic duplication.

Author

Filser, Mathilde, Schwartz, Mathias, Merchadou, Kevin, Hamza, Abderaouf, Villy, Marie-Charlotte, Decees, Antoine, Frouin, Eléonore, Girard, Elodie, Caputo, Sandrine M, Renault, Victor, Becette, Véronique, Golmard, Lisa, Servant, Nicolas, Stoppa-Lyonnet, Dominique, Delattre, Olivier, Colas, Chrystelle, and Masliah-Planchon, Julien

Abstract

BRCA1 and BRCA2 are tumour suppressor genes that have been characterised as predisposition genes for the development of hereditary breast and ovarian cancers among other malignancies. The molecular diagnosis of this predisposition syndrome is based on the detection of inactivating variants of any type in those genes. But in the case of structural variants, functional consequences can be difficult to assess using standard molecular methods, as the precise resolution of their sequence is often impossible with short-read next generation sequencing techniques. It has been recently demonstrated that Oxford Nanopore long read sequencing technology can accurately and rapidly provide genetic diagnoses of Mendelian diseases, including those linked to pathogenic structural variants. Here, we report the accurate resolution of a germline duplication event of exons 18–20 of BRCA1 using Nanopore sequencing with adaptive sampling target enrichment. This allowed us to classify this variant as pathogenic within a short timeframe of 10 days. This study provides a proof-of-concept that nanopore adaptive sampling is a highly efficient technique for the investigation of structural variants of tumour suppressor genes in a clinical context. [ABSTRACT FROM AUTHOR]

Published
2023
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20. Supplementary Figure 4. (A-D) from Combining Homologous Recombination and Phosphopeptide-binding Data to Predict the Impact of BRCA1 BRCT Variants on Cancer Risk

Author

Petitalot, Ambre, primary, Dardillac, Elodie, primary, Jacquet, Eric, primary, Nhiri, Naima, primary, Guirouilh-Barbat, Josée, primary, Julien, Patrick, primary, Bouazzaoui, Isslam, primary, Bonte, Dorine, primary, Feunteun, Jean, primary, Schnell, Jeff A., primary, Lafitte, Philippe, primary, Aude, Jean-Christophe, primary, Noguès, Catherine, primary, Rouleau, Etienne, primary, Lidereau, Rosette, primary, Lopez, Bernard S., primary, Zinn-Justin, Sophie, primary, and Caputo, Sandrine M., primary

Published
2023
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21. Data from Combining Homologous Recombination and Phosphopeptide-binding Data to Predict the Impact of BRCA1 BRCT Variants on Cancer Risk

Author

Petitalot, Ambre, primary, Dardillac, Elodie, primary, Jacquet, Eric, primary, Nhiri, Naima, primary, Guirouilh-Barbat, Josée, primary, Julien, Patrick, primary, Bouazzaoui, Isslam, primary, Bonte, Dorine, primary, Feunteun, Jean, primary, Schnell, Jeff A., primary, Lafitte, Philippe, primary, Aude, Jean-Christophe, primary, Noguès, Catherine, primary, Rouleau, Etienne, primary, Lidereau, Rosette, primary, Lopez, Bernard S., primary, Zinn-Justin, Sophie, primary, and Caputo, Sandrine M., primary

Published
2023
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22. Supplementary Figure 6. (A) from Combining Homologous Recombination and Phosphopeptide-binding Data to Predict the Impact of BRCA1 BRCT Variants on Cancer Risk

Author

Petitalot, Ambre, primary, Dardillac, Elodie, primary, Jacquet, Eric, primary, Nhiri, Naima, primary, Guirouilh-Barbat, Josée, primary, Julien, Patrick, primary, Bouazzaoui, Isslam, primary, Bonte, Dorine, primary, Feunteun, Jean, primary, Schnell, Jeff A., primary, Lafitte, Philippe, primary, Aude, Jean-Christophe, primary, Noguès, Catherine, primary, Rouleau, Etienne, primary, Lidereau, Rosette, primary, Lopez, Bernard S., primary, Zinn-Justin, Sophie, primary, and Caputo, Sandrine M., primary

Published
2023
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23. Supp tables from Combining Homologous Recombination and Phosphopeptide-binding Data to Predict the Impact of BRCA1 BRCT Variants on Cancer Risk

Author

Petitalot, Ambre, primary, Dardillac, Elodie, primary, Jacquet, Eric, primary, Nhiri, Naima, primary, Guirouilh-Barbat, Josée, primary, Julien, Patrick, primary, Bouazzaoui, Isslam, primary, Bonte, Dorine, primary, Feunteun, Jean, primary, Schnell, Jeff A., primary, Lafitte, Philippe, primary, Aude, Jean-Christophe, primary, Noguès, Catherine, primary, Rouleau, Etienne, primary, Lidereau, Rosette, primary, Lopez, Bernard S., primary, Zinn-Justin, Sophie, primary, and Caputo, Sandrine M., primary

Published
2023
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24. Supplementary Figure 1 (B). from Combining Homologous Recombination and Phosphopeptide-binding Data to Predict the Impact of BRCA1 BRCT Variants on Cancer Risk

Author

Petitalot, Ambre, primary, Dardillac, Elodie, primary, Jacquet, Eric, primary, Nhiri, Naima, primary, Guirouilh-Barbat, Josée, primary, Julien, Patrick, primary, Bouazzaoui, Isslam, primary, Bonte, Dorine, primary, Feunteun, Jean, primary, Schnell, Jeff A., primary, Lafitte, Philippe, primary, Aude, Jean-Christophe, primary, Noguès, Catherine, primary, Rouleau, Etienne, primary, Lidereau, Rosette, primary, Lopez, Bernard S., primary, Zinn-Justin, Sophie, primary, and Caputo, Sandrine M., primary

Published
2023
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25. Supplementary Figure 6. (B-C) from Combining Homologous Recombination and Phosphopeptide-binding Data to Predict the Impact of BRCA1 BRCT Variants on Cancer Risk

Author

Petitalot, Ambre, primary, Dardillac, Elodie, primary, Jacquet, Eric, primary, Nhiri, Naima, primary, Guirouilh-Barbat, Josée, primary, Julien, Patrick, primary, Bouazzaoui, Isslam, primary, Bonte, Dorine, primary, Feunteun, Jean, primary, Schnell, Jeff A., primary, Lafitte, Philippe, primary, Aude, Jean-Christophe, primary, Noguès, Catherine, primary, Rouleau, Etienne, primary, Lidereau, Rosette, primary, Lopez, Bernard S., primary, Zinn-Justin, Sophie, primary, and Caputo, Sandrine M., primary

Published
2023
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26. Supplementary Figure 2. Classification of the VUS as a function of the impact of the corresponding missense variations on BRCT domain expression in E. coli. from Combining Homologous Recombination and Phosphopeptide-binding Data to Predict the Impact of BRCA1 BRCT Variants on Cancer Risk

Author

Petitalot, Ambre, primary, Dardillac, Elodie, primary, Jacquet, Eric, primary, Nhiri, Naima, primary, Guirouilh-Barbat, Josée, primary, Julien, Patrick, primary, Bouazzaoui, Isslam, primary, Bonte, Dorine, primary, Feunteun, Jean, primary, Schnell, Jeff A., primary, Lafitte, Philippe, primary, Aude, Jean-Christophe, primary, Noguès, Catherine, primary, Rouleau, Etienne, primary, Lidereau, Rosette, primary, Lopez, Bernard S., primary, Zinn-Justin, Sophie, primary, and Caputo, Sandrine M., primary

Published
2023
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27. Supplementary Figure 3. Classification of the 42 purified mutated BRCT domains as a function of their thermostability as measured using a high throughput fluorescence assay. from Combining Homologous Recombination and Phosphopeptide-binding Data to Predict the Impact of BRCA1 BRCT Variants on Cancer Risk

Author

Petitalot, Ambre, primary, Dardillac, Elodie, primary, Jacquet, Eric, primary, Nhiri, Naima, primary, Guirouilh-Barbat, Josée, primary, Julien, Patrick, primary, Bouazzaoui, Isslam, primary, Bonte, Dorine, primary, Feunteun, Jean, primary, Schnell, Jeff A., primary, Lafitte, Philippe, primary, Aude, Jean-Christophe, primary, Noguès, Catherine, primary, Rouleau, Etienne, primary, Lidereau, Rosette, primary, Lopez, Bernard S., primary, Zinn-Justin, Sophie, primary, and Caputo, Sandrine M., primary

Published
2023
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28. Supplementary Figure 5. (A-B) from Combining Homologous Recombination and Phosphopeptide-binding Data to Predict the Impact of BRCA1 BRCT Variants on Cancer Risk

Author

Petitalot, Ambre, primary, Dardillac, Elodie, primary, Jacquet, Eric, primary, Nhiri, Naima, primary, Guirouilh-Barbat, Josée, primary, Julien, Patrick, primary, Bouazzaoui, Isslam, primary, Bonte, Dorine, primary, Feunteun, Jean, primary, Schnell, Jeff A., primary, Lafitte, Philippe, primary, Aude, Jean-Christophe, primary, Noguès, Catherine, primary, Rouleau, Etienne, primary, Lidereau, Rosette, primary, Lopez, Bernard S., primary, Zinn-Justin, Sophie, primary, and Caputo, Sandrine M., primary

Published
2023
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29. Supplementary Figure 1 (A). from Combining Homologous Recombination and Phosphopeptide-binding Data to Predict the Impact of BRCA1 BRCT Variants on Cancer Risk

Author

Petitalot, Ambre, primary, Dardillac, Elodie, primary, Jacquet, Eric, primary, Nhiri, Naima, primary, Guirouilh-Barbat, Josée, primary, Julien, Patrick, primary, Bouazzaoui, Isslam, primary, Bonte, Dorine, primary, Feunteun, Jean, primary, Schnell, Jeff A., primary, Lafitte, Philippe, primary, Aude, Jean-Christophe, primary, Noguès, Catherine, primary, Rouleau, Etienne, primary, Lidereau, Rosette, primary, Lopez, Bernard S., primary, Zinn-Justin, Sophie, primary, and Caputo, Sandrine M., primary

Published
2023
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30. Supplementary Data from Skipping Nonsense to Maintain Function: The Paradigm of BRCA2 Exon 12

Author

Meulemans, Laëtitia, primary, Mesman, Romy L.S., primary, Caputo, Sandrine M., primary, Krieger, Sophie, primary, Guillaud-Bataille, Marine, primary, Caux-Moncoutier, Virginie, primary, Léone, Mélanie, primary, Boutry-Kryza, Nadia, primary, Sokolowska, Johanna, primary, Révillion, Françoise, primary, Delnatte, Capucine, primary, Tubeuf, Hélène, primary, Soukarieh, Omar, primary, Bonnet-Dorion, Françoise, primary, Guibert, Virginie, primary, Bronner, Myriam, primary, Bourdon, Violaine, primary, Lizard, Sarab, primary, Vilquin, Paul, primary, Privat, Maud, primary, Drouet, Aurélie, primary, Grout, Charlotte, primary, Calléja, Fabienne M.G.R., primary, Golmard, Lisa, primary, Vrieling, Harry, primary, Stoppa-Lyonnet, Dominique, primary, Houdayer, Claude, primary, Frebourg, Thierry, primary, Vreeswijk, Maaike P.G., primary, Martins, Alexandra, primary, and Gaildrat, Pascaline, primary

Published
2023
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31. Supplementary Tables from Calibration of Pathogenicity Due to Variant-Induced Leaky Splicing Defects by Using BRCA2 Exon 3 as a Model System

Author

Tubeuf, Hélène, primary, Caputo, Sandrine M., primary, Sullivan, Teresa, primary, Rondeaux, Julie, primary, Krieger, Sophie, primary, Caux-Moncoutier, Virginie, primary, Hauchard, Julie, primary, Castelain, Gaia, primary, Fiévet, Alice, primary, Meulemans, Laëtitia, primary, Révillion, Françoise, primary, Léoné, Mélanie, primary, Boutry-Kryza, Nadia, primary, Delnatte, Capucine, primary, Guillaud-Bataille, Marine, primary, Cleveland, Linda, primary, Reid, Susan, primary, Southon, Eileen, primary, Soukarieh, Omar, primary, Drouet, Aurélie, primary, Di Giacomo, Daniela, primary, Vezain, Myriam, primary, Bonnet-Dorion, Françoise, primary, Bourdon, Violaine, primary, Larbre, Hélène, primary, Muller, Danièle, primary, Pujol, Pascal, primary, Vaz, Fátima, primary, Audebert-Bellanger, Séverine, primary, Colas, Chrystelle, primary, Venat-Bouvet, Laurence, primary, Solano, Angela R., primary, Stoppa-Lyonnet, Dominique, primary, Houdayer, Claude, primary, Frebourg, Thierry, primary, Gaildrat, Pascaline, primary, Sharan, Shyam K., primary, and Martins, Alexandra, primary

Published
2023
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32. Data from Skipping Nonsense to Maintain Function: The Paradigm of BRCA2 Exon 12

Author

Meulemans, Laëtitia, primary, Mesman, Romy L.S., primary, Caputo, Sandrine M., primary, Krieger, Sophie, primary, Guillaud-Bataille, Marine, primary, Caux-Moncoutier, Virginie, primary, Léone, Mélanie, primary, Boutry-Kryza, Nadia, primary, Sokolowska, Johanna, primary, Révillion, Françoise, primary, Delnatte, Capucine, primary, Tubeuf, Hélène, primary, Soukarieh, Omar, primary, Bonnet-Dorion, Françoise, primary, Guibert, Virginie, primary, Bronner, Myriam, primary, Bourdon, Violaine, primary, Lizard, Sarab, primary, Vilquin, Paul, primary, Privat, Maud, primary, Drouet, Aurélie, primary, Grout, Charlotte, primary, Calléja, Fabienne M.G.R., primary, Golmard, Lisa, primary, Vrieling, Harry, primary, Stoppa-Lyonnet, Dominique, primary, Houdayer, Claude, primary, Frebourg, Thierry, primary, Vreeswijk, Maaike P.G., primary, Martins, Alexandra, primary, and Gaildrat, Pascaline, primary

Published
2023
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33. Supplementary Data Tables S1-S4 from Skipping Nonsense to Maintain Function: The Paradigm of BRCA2 Exon 12

Author

Meulemans, Laëtitia, primary, Mesman, Romy L.S., primary, Caputo, Sandrine M., primary, Krieger, Sophie, primary, Guillaud-Bataille, Marine, primary, Caux-Moncoutier, Virginie, primary, Léone, Mélanie, primary, Boutry-Kryza, Nadia, primary, Sokolowska, Johanna, primary, Révillion, Françoise, primary, Delnatte, Capucine, primary, Tubeuf, Hélène, primary, Soukarieh, Omar, primary, Bonnet-Dorion, Françoise, primary, Guibert, Virginie, primary, Bronner, Myriam, primary, Bourdon, Violaine, primary, Lizard, Sarab, primary, Vilquin, Paul, primary, Privat, Maud, primary, Drouet, Aurélie, primary, Grout, Charlotte, primary, Calléja, Fabienne M.G.R., primary, Golmard, Lisa, primary, Vrieling, Harry, primary, Stoppa-Lyonnet, Dominique, primary, Houdayer, Claude, primary, Frebourg, Thierry, primary, Vreeswijk, Maaike P.G., primary, Martins, Alexandra, primary, and Gaildrat, Pascaline, primary

Published
2023
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34. Data from Calibration of Pathogenicity Due to Variant-Induced Leaky Splicing Defects by Using BRCA2 Exon 3 as a Model System

Author

Tubeuf, Hélène, primary, Caputo, Sandrine M., primary, Sullivan, Teresa, primary, Rondeaux, Julie, primary, Krieger, Sophie, primary, Caux-Moncoutier, Virginie, primary, Hauchard, Julie, primary, Castelain, Gaia, primary, Fiévet, Alice, primary, Meulemans, Laëtitia, primary, Révillion, Françoise, primary, Léoné, Mélanie, primary, Boutry-Kryza, Nadia, primary, Delnatte, Capucine, primary, Guillaud-Bataille, Marine, primary, Cleveland, Linda, primary, Reid, Susan, primary, Southon, Eileen, primary, Soukarieh, Omar, primary, Drouet, Aurélie, primary, Di Giacomo, Daniela, primary, Vezain, Myriam, primary, Bonnet-Dorion, Françoise, primary, Bourdon, Violaine, primary, Larbre, Hélène, primary, Muller, Danièle, primary, Pujol, Pascal, primary, Vaz, Fátima, primary, Audebert-Bellanger, Séverine, primary, Colas, Chrystelle, primary, Venat-Bouvet, Laurence, primary, Solano, Angela R., primary, Stoppa-Lyonnet, Dominique, primary, Houdayer, Claude, primary, Frebourg, Thierry, primary, Gaildrat, Pascaline, primary, Sharan, Shyam K., primary, and Martins, Alexandra, primary

Published
2023
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35. Supplementary Data from Calibration of Pathogenicity Due to Variant-Induced Leaky Splicing Defects by Using BRCA2 Exon 3 as a Model System

Author

Tubeuf, Hélène, primary, Caputo, Sandrine M., primary, Sullivan, Teresa, primary, Rondeaux, Julie, primary, Krieger, Sophie, primary, Caux-Moncoutier, Virginie, primary, Hauchard, Julie, primary, Castelain, Gaia, primary, Fiévet, Alice, primary, Meulemans, Laëtitia, primary, Révillion, Françoise, primary, Léoné, Mélanie, primary, Boutry-Kryza, Nadia, primary, Delnatte, Capucine, primary, Guillaud-Bataille, Marine, primary, Cleveland, Linda, primary, Reid, Susan, primary, Southon, Eileen, primary, Soukarieh, Omar, primary, Drouet, Aurélie, primary, Di Giacomo, Daniela, primary, Vezain, Myriam, primary, Bonnet-Dorion, Françoise, primary, Bourdon, Violaine, primary, Larbre, Hélène, primary, Muller, Danièle, primary, Pujol, Pascal, primary, Vaz, Fátima, primary, Audebert-Bellanger, Séverine, primary, Colas, Chrystelle, primary, Venat-Bouvet, Laurence, primary, Solano, Angela R., primary, Stoppa-Lyonnet, Dominique, primary, Houdayer, Claude, primary, Frebourg, Thierry, primary, Gaildrat, Pascaline, primary, Sharan, Shyam K., primary, and Martins, Alexandra, primary

Published
2023
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36. A likelihood ratio approach for utilizing case-control data in the clinical classification of rare sequence variants:Application to BRCA1 and BRCA2

Author

Zanti, Maria, O'Mahony, Denise G., Parsons, Michael T., Li, Hongyan, Dennis, Joe, Aittomäkkiki, Kristiina, Andrulis, Irene L., Anton-Culver, Hoda, Aronson, Kristan J., Augustinsson, Annelie, Becher, Heiko, Bojesen, Stig E., Bolla, Manjeet K., Brenner, Hermann, Brown, Melissa A., Buys, Saundra S., Canzian, Federico, Caputo, Sandrine M., Castelao, Jose E., Chang-Claude, Jenny, Czene, Kamila, Daly, Mary B., De Nicolo, Arcangela, Devilee, Peter, Dörk, Thilo, Dunning, Alison M., Dwek, Miriam, Eccles, Diana M., Engel, Christoph, Gareth Evans, D., Fasching, Peter A., Gago-Dominguez, Manuela, García-Closas, Montserrat, García-Sáenz, José A., Gentry-Maharaj, Aleksandra, Geurts-Giele, Willemina R.R., Giles, Graham G., Glendon, Gord, Goldberg, Mark S., Gómez Garcia, Encarna B., Göendert, Melanie, Guénel, Pascal, Hahnen, Eric, Haiman, Christopher A., Hall, Per, Hamann, Ute, Harkness, Elaine F., Hogervorst, Frans B.L., Hollestelle, Antoinette, Hoppe, Reiner, Hopper, John L., Houdayer, Claude, Houlston, Richard S., Howell, Anthony, Jakimovska, Milena, Jakubowska, Anna, Jernström, Helena, John, Esther M., Kaaks, Rudolf, Kitahara, Cari M., Koutros, Stella, Kraft, Peter, Kristensen, Vessela N., Lacey, James V., Lambrechts, Diether, Léoné, Melanie, Lindblom, Annika, Lubiski, Jan, Lush, Michael, Mannermaa, Arto, Manoochehri, Mehdi, Manoukian, Siranoush, Margolin, Sara, Martinez, Maria Elena, Menon, Usha, Milne, Roger L., Monteiro, Alvaro N., Murphy, Rachel A., Neuhausen, Susan L., Nevanlinna, Heli, Newman, William G., Offit, Kenneth, Park, Sue K., James, Paul, Peterlongo, Paolo, Peto, Julian, Plaseska-Karanfilska, Dijana, Punie, Kevin, Radice, Paolo, Rashid, Muhammad U., Rennert, Gad, Romero, Atocha, Rosenberg, Efraim H., Saloustros, Emmanouil, Sandler, Dale P., Schmidt, Marjanka K., Schmutzler, Rita K., Shu, Xiao Ou, Simard, Jacques, Southey, Melissa C., Stone, Jennifer, Stoppa-Lyonnet, Dominique, Tamimi, Rulla M., Tapper, William J., Taylor, Jack A., Teo, Soo Hwang, Teras, Lauren R., Terry, Mary Beth, Thomassen, Mads, Troester, Melissa A., Vachon, Celine M., Vega, Ana, Vreeswijk, Maaike P.G., Wang, Qin, Wappenschmidt, Barbara, Weinberg, Clarice R., Wolk, Alicja, Zheng, Wei, Feng, Bingjian, Couch, Fergus J., Spurdle, Amanda B., Easton, Douglas F., Goldgar, David E., Michailidou, Kyriaki, Zanti, Maria, O'Mahony, Denise G., Parsons, Michael T., Li, Hongyan, Dennis, Joe, Aittomäkkiki, Kristiina, Andrulis, Irene L., Anton-Culver, Hoda, Aronson, Kristan J., Augustinsson, Annelie, Becher, Heiko, Bojesen, Stig E., Bolla, Manjeet K., Brenner, Hermann, Brown, Melissa A., Buys, Saundra S., Canzian, Federico, Caputo, Sandrine M., Castelao, Jose E., Chang-Claude, Jenny, Czene, Kamila, Daly, Mary B., De Nicolo, Arcangela, Devilee, Peter, Dörk, Thilo, Dunning, Alison M., Dwek, Miriam, Eccles, Diana M., Engel, Christoph, Gareth Evans, D., Fasching, Peter A., Gago-Dominguez, Manuela, García-Closas, Montserrat, García-Sáenz, José A., Gentry-Maharaj, Aleksandra, Geurts-Giele, Willemina R.R., Giles, Graham G., Glendon, Gord, Goldberg, Mark S., Gómez Garcia, Encarna B., Göendert, Melanie, Guénel, Pascal, Hahnen, Eric, Haiman, Christopher A., Hall, Per, Hamann, Ute, Harkness, Elaine F., Hogervorst, Frans B.L., Hollestelle, Antoinette, Hoppe, Reiner, Hopper, John L., Houdayer, Claude, Houlston, Richard S., Howell, Anthony, Jakimovska, Milena, Jakubowska, Anna, Jernström, Helena, John, Esther M., Kaaks, Rudolf, Kitahara, Cari M., Koutros, Stella, Kraft, Peter, Kristensen, Vessela N., Lacey, James V., Lambrechts, Diether, Léoné, Melanie, Lindblom, Annika, Lubiski, Jan, Lush, Michael, Mannermaa, Arto, Manoochehri, Mehdi, Manoukian, Siranoush, Margolin, Sara, Martinez, Maria Elena, Menon, Usha, Milne, Roger L., Monteiro, Alvaro N., Murphy, Rachel A., Neuhausen, Susan L., Nevanlinna, Heli, Newman, William G., Offit, Kenneth, Park, Sue K., James, Paul, Peterlongo, Paolo, Peto, Julian, Plaseska-Karanfilska, Dijana, Punie, Kevin, Radice, Paolo, Rashid, Muhammad U., Rennert, Gad, Romero, Atocha, Rosenberg, Efraim H., Saloustros, Emmanouil, Sandler, Dale P., Schmidt, Marjanka K., Schmutzler, Rita K., Shu, Xiao Ou, Simard, Jacques, Southey, Melissa C., Stone, Jennifer, Stoppa-Lyonnet, Dominique, Tamimi, Rulla M., Tapper, William J., Taylor, Jack A., Teo, Soo Hwang, Teras, Lauren R., Terry, Mary Beth, Thomassen, Mads, Troester, Melissa A., Vachon, Celine M., Vega, Ana, Vreeswijk, Maaike P.G., Wang, Qin, Wappenschmidt, Barbara, Weinberg, Clarice R., Wolk, Alicja, Zheng, Wei, Feng, Bingjian, Couch, Fergus J., Spurdle, Amanda B., Easton, Douglas F., Goldgar, David E., and Michailidou, Kyriaki

Abstract

A large number of variants identified through clinical genetic testing in disease susceptibility genes are of uncertain significance (VUS). Following the recommendations of the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP), the frequency in case-control datasets (PS4 criterion) can inform their interpretation. We present a novel case-control likelihood ratio-based method that incorporates gene-specific age-related penetrance. We demonstrate the utility of this method in the analysis of simulated and real datasets. In the analysis of simulated data, the likelihood ratio method was more powerful compared to other methods. Likelihood ratios were calculated for a case-control dataset of BRCA1 and BRCA2 variants from the Breast Cancer Association Consortium (BCAC) and compared with logistic regression results. A larger number of variants reached evidence in favor of pathogenicity, and a substantial number of variants had evidence against pathogenicity findings that would not have been reached using other case-control analysis methods. Our novel method provides greater power to classify rare variants compared with classical case-control methods. As an initiative from the ENIGMA Analytical Working Group, we provide user-friendly scripts and preformatted Excel calculators for implementation of the method for rare variants in BRCA1, BRCA2, and other high-risk genes with known penetrance.

Published
2023

37. Mosaic BRCA1promoter methylation contribution in hereditary breast/ovarian cancer pedigrees

Author

Schwartz, Mathias, Ibadioune, Sabrina, Chansavang, Albain, Vacher, Sophie, Caputo, Sandrine M, Delhomelle, Hélène, Wong, Jennifer, Abidallah, Khadija, Moncoutier, Virginie, Becette, Véronique, Popova, Tatiana, Suybeng, Voreak, De Pauw, Antoine, Stern, Marc-Henri, Colas, Chrystelle, Mouret-Fourme, Emmanuelle, Stoppa-Lyonnet, Dominique, Golmard, Lisa, Bieche, Ivan, and Masliah-Planchon, Julien

Abstract

PurposeMosaic BRCA1promoter methylation (BRCA1meth) increases the risk of early-onset breast cancer, triple-negative breast cancer and ovarian cancer. As mosaic BRCA1meth are believed to occur de novo, their role in family breast/ovarian cancer has not been assessed.PatientsBlood-derived DNA from 20 unrelated affected cases from families with aggregation of breast/ovarian cancer, but with no germline pathogenic variants in BRCA1/2, PALB2or RAD51C/D, were screened by methylation-sensitive high-resolution melting. CpG analysis was performed by pyrosequencing on blood and buccal swab. Two probands carried a pathogenic variant in a moderate-penetrance gene (ATMand BARD1), and 8 of 18 others (44%) carried BRCA1meth (vs none of the 20 age-matched controls). Involvement of BRCA1in tumourigenesis in methylated probands was demonstrated in most tested cases by detection of a loss of heterozygosity and a homologous recombination deficiency signature. Among the eight methylated probands, two had relatives with breast cancer with detectable BRCA1meth in blood, including one with high methylation levels in two non-tumour tissues.ConclusionsThe high prevalence of mosaic BRCA1meth in patients with breast/ovarian cancer with affected relatives, as well as this first description of a family aggregation of mosaic BRCA1meth, shows how this de novo event can contribute to hereditary breast/ovarian cancer pedigrees.

Published
2024
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38. Germline HPF1retrogene insertion in RB1gene involved in cancer predisposition

Author

Le Gall, Jessica, Dehainault, Catherine, Boutte, Matteo, Petitalot, Ambre, Caputo, Sandrine M, Courtois, Laura, Vacher, Sophie, Bieche, Ivan, Radvanyi, Francois, Pacquement, Hélène, Doz, Francois, Lumbroso-Le Rouic, Livia, Gauthier Villars, Marion, Stoppa-Lyonnet, Dominique, Lallemand, Francois, Houdayer, Claude, and Golmard, Lisa

Abstract

About half of the human genome is composed of repeated sequences derived from mobile elements, mainly retrotransposons, generally without pathogenic effect. Familial forms of retinoblastoma are caused by germline pathogenic variants in RB1gene. Here, we describe a family with retinoblastoma affecting a father and his son. No pathogenic variant was identified after DNA analysis of RB1gene coding sequence and exon-intron junctions. However, RB1mRNA analysis showed a chimeric transcript with insertion of 114 nucleotides from HPF1gene inside RB1gene. This chimeric transcript led to an insertion of 38 amino acids in functional domain of retinoblastoma protein. Subsequent DNA analysis in RB1intron 17 revealed the presence of a full-length HPF1retrogene insertion in opposite orientation. Functional assay shows that this insertion has a deleterious impact on retinoblastoma protein function. This is the first report of a full-length retrogene insertion involved in human Mendelian disease leading to a chimeric transcript and a non-functional chimeric protein. Some retrogene insertions may be missed by standard diagnostic genetic testing, so contribution of retrogene insertions to human disease may be underestimated. The increasing use of whole genome sequencing in diagnostic settings will help to get a more comprehensive view of retrogenes.

Published
2024
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39. Identification of a large intra-exonic deletion in BRCA2 exon 18 in a pancreatic ductal adenocarcinoma

Author

Debbabi, Inès, primary, Vacher, Sophie, additional, Neuzillet, Cindy, additional, Cros, Jérome, additional, Revillon, Françoise, additional, Petitalot, Ambre, additional, Turpin, Anthony, additional, Antonio, Samantha, additional, Girard, Elodie, additional, Dupain, Célia, additional, Kamal, Maud, additional, Hammel, Pascal, additional, Bièche, Ivan, additional, Masliah-Planchon, Julien, additional, and Caputo, Sandrine M., additional

Published
2023
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40. sj-docx-1-tam-10.1177_17588359221146132 – Supplemental material for Identification of a large intra-exonic deletion in BRCA2 exon 18 in a pancreatic ductal adenocarcinoma

Author

Debbabi, Inès, Vacher, Sophie, Neuzillet, Cindy, Cros, Jérome, Revillon, Françoise, Petitalot, Ambre, Turpin, Anthony, Antonio, Samantha, Girard, Elodie, Dupain, Célia, Kamal, Maud, Hammel, Pascal, Bièche, Ivan, Masliah-Planchon, Julien, and Caputo, Sandrine M.

Subjects
110203 Respiratory Diseases, FOS: Clinical medicine, 111702 Aged Health Care, FOS: Health sciences, 111599 Pharmacology and Pharmaceutical Sciences not elsewhere classified, 111299 Oncology and Carcinogenesis not elsewhere classified
Abstract

Supplemental material, sj-docx-1-tam-10.1177_17588359221146132 for Identification of a large intra-exonic deletion in BRCA2 exon 18 in a pancreatic ductal adenocarcinoma by Inès Debbabi, Sophie Vacher, Cindy Neuzillet, Jérome Cros, Françoise Revillon, Ambre Petitalot, Anthony Turpin, Samantha Antonio, Elodie Girard, Célia Dupain, Maud Kamal, Pascal Hammel, Ivan Bièche, Julien Masliah-Planchon and Sandrine M. Caputo in Therapeutic Advances in Medical Oncology

Published
2023
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41. sj-pptx-2-tam-10.1177_17588359221146132 – Supplemental material for Identification of a large intra-exonic deletion in BRCA2 exon 18 in a pancreatic ductal adenocarcinoma

Author

Debbabi, Inès, Vacher, Sophie, Neuzillet, Cindy, Cros, Jérome, Revillon, Françoise, Petitalot, Ambre, Turpin, Anthony, Antonio, Samantha, Girard, Elodie, Dupain, Célia, Kamal, Maud, Hammel, Pascal, Bièche, Ivan, Masliah-Planchon, Julien, and Caputo, Sandrine M.

Subjects
110203 Respiratory Diseases, FOS: Clinical medicine, 111702 Aged Health Care, FOS: Health sciences, 111599 Pharmacology and Pharmaceutical Sciences not elsewhere classified, 111299 Oncology and Carcinogenesis not elsewhere classified
Abstract

Supplemental material, sj-pptx-2-tam-10.1177_17588359221146132 for Identification of a large intra-exonic deletion in BRCA2 exon 18 in a pancreatic ductal adenocarcinoma by Inès Debbabi, Sophie Vacher, Cindy Neuzillet, Jérome Cros, Françoise Revillon, Ambre Petitalot, Anthony Turpin, Samantha Antonio, Elodie Girard, Célia Dupain, Maud Kamal, Pascal Hammel, Ivan Bièche, Julien Masliah-Planchon and Sandrine M. Caputo in Therapeutic Advances in Medical Oncology

Published
2023
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42. SPiP: Splicing Prediction Pipeline, a machine learning tool for massive detection of exonic and intronic variant effects on mRNA splicing

Author

Leman, Raphaël, primary, Parfait, Béatrice, additional, Vidaud, Dominique, additional, Girodon, Emmanuelle, additional, Pacot, Laurence, additional, Le Gac, Gérald, additional, Ka, Chandran, additional, Ferec, Claude, additional, Fichou, Yann, additional, Quesnelle, Céline, additional, Aucouturier, Camille, additional, Muller, Etienne, additional, Vaur, Dominique, additional, Castera, Laurent, additional, Boulouard, Flavie, additional, Ricou, Agathe, additional, Tubeuf, Hélène, additional, Soukarieh, Omar, additional, Gaildrat, Pascaline, additional, Riant, Florence, additional, Guillaud‐Bataille, Marine, additional, Caputo, Sandrine M., additional, Caux‐Moncoutier, Virginie, additional, Boutry‐Kryza, Nadia, additional, Bonnet‐Dorion, Françoise, additional, Schultz, Ines, additional, Rossing, Maria, additional, Quenez, Olivier, additional, Goldenberg, Louis, additional, Harter, Valentin, additional, Parsons, Michael T., additional, Spurdle, Amanda B., additional, Frébourg, Thierry, additional, Martins, Alexandra, additional, Houdayer, Claude, additional, and Krieger, Sophie, additional

Published
2022
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43. Risks of breast and ovarian cancer for women harboring pathogenic missense variants in BRCA1 and BRCA2 compared with those harboring protein truncating variants

Author

Li, Hongyan, primary, Engel, Christoph, additional, Hoya, Miguel de la, additional, Peterlongo, Paolo, additional, Yannoukakos, Drakoulis, additional, Livraghi, Luca, additional, Radice, Paolo, additional, Thomassen, Mads, additional, Hansen, Thomas V.O., additional, Gerdes, Anne-Marie, additional, Nielsen, Henriette R., additional, Caputo, Sandrine M., additional, Zambelli, Alberto, additional, Borg, Ake, additional, Solano, Angela, additional, Thomas, Abigail, additional, Parsons, Michael T., additional, Antoniou, Antonis C., additional, Leslie, Goska, additional, Yang, Xin, additional, Chenevix-Trench, Georgia, additional, Caldes, Trinidad, additional, Kwong, Ava, additional, Pedersen, Inge Søkilde, additional, Lautrup, Charlotte K., additional, John, Esther M., additional, Terry, Mary Beth, additional, Hopper, John L., additional, Southey, Melissa C., additional, Andrulis, Irene L., additional, Tischkowitz, Marc, additional, Janavicius, Ramunas, additional, Boonen, Susanne E., additional, Kroeldrup, Lone, additional, Varesco, Liliana, additional, Hamann, Ute, additional, Vega, Ana, additional, Palmero, Edenir I., additional, Garber, Judy, additional, Montagna, Marco, additional, Van Asperen, Christi J., additional, Foretova, Lenka, additional, Greene, Mark H., additional, Selkirk, Tina, additional, Moller, Pal, additional, Toland, Amanda E., additional, Domchek, Susan M., additional, James, Paul A., additional, Thorne, Heather, additional, Eccles, Diana M., additional, Nielsen, Sarah M., additional, Manoukian, Siranoush, additional, Pasini, Barbara, additional, Caligo, Maria A., additional, Lazaro, Conxi, additional, Kirk, Judy, additional, Wappenschmidt, Barbara, additional, Spurdle, Amanda B., additional, Couch, Fergus J., additional, Schmutzler, Rita, additional, and Goldgar, David E., additional

Published
2022
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44. The BRCA1 c. 5096G>A p.Arg1699Gln (R1699Q) intermediate risk variant: breast and ovarian cancer risk estimation and recommendations for clinical management from the ENIGMA consortium

Author

Moghadasi, Setareh, Meeks, Huong D, Vreeswijk, Maaike PG, Janssen, Linda AM, Borg, Åke, Ehrencrona, Hans, Paulsson-Karlsson, Ylva, Wappenschmidt, Barbara, Engel, Christoph, Gehrig, Andrea, Arnold, Norbert, Hansen, Thomas Van Overeem, Thomassen, Mads, Jensen, Uffe Birk, Kruse, Torben A, Ejlertsen, Bent, Gerdes, Anne-Marie, Pedersen, Inge Søkilde, Caputo, Sandrine M, Couch, Fergus, Hallberg, Emily J, van den Ouweland, Ans MW, Collée, Margriet J, Teugels, Erik, Adank, Muriel A, van der Luijt, Rob B, Mensenkamp, Arjen R, Oosterwijk, Jan C, Blok, Marinus J, Janin, Nicolas, Claes, Kathleen BM, Tucker, Kathy, Viassolo, Valeria, Toland, Amanda Ewart, Eccles, Diana E, Devilee, Peter, Van Asperen, Christie J, Spurdle, Amanda B, Goldgar, David E, and García, Encarna Gómez

Published
2018
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45. Risks of breast and ovarian cancer for women harboring pathogenic missense variants in BRCA1 and BRCA2 compared with those harboring protein truncating variants

Author

Li, Hongyan, Engel, Christoph, de la Hoya, Miguel, Peterlongo, Paolo, Yannoukakos, Drakoulis, Livraghi, Luca, Radice, Paolo, Thomassen, Mads, Hansen, Thomas V. O., Gerdes, Anne-Marie, Nielsen, Henriette R., Caputo, Sandrine M., Zambelli, Alberto, Borg, Ake, Solano, Angela, Thomas, Abigail, Parsons, Michael T., Antoniou, Antonis C., Leslie, Goska, Yang, Xin, Chenevix-Trench, Georgia, Caldes, Trinidad, Kwong, Ava, Pedersen, Inge Sokilde, Lautrup, Charlotte K., John, Esther M., Terry, Mary Beth, Hopper, John L., Southey, Melissa C., Andrulis, Irene L., Tischkowitz, Marc, Janavicius, Ramunas, Boonen, Susanne E., Kroeldrup, Lone, Varesco, Liliana, Hamann, Ute, Vega, Ana, Palmero, Edenir, I, Garber, Judy, Montagna, Marco, Van Asperen, Christi J., Foretova, Lenka, Greene, Mark H., Selkirk, Tina, Moller, Pal, Toland, Amanda E., Domchek, Susan M., James, Paul A., Thorne, Heather, Eccles, Diana M., Nielsen, Sarah M., Manoukian, Siranoush, Pasini, Barbara, Caligo, Maria A., Lazaro, Conxi, Kirk, Judy, Wappenschmidt, Barbara, Spurdle, Amanda B., Couch, Fergus J., Schmutzler, Rita, Goldgar, David E., Li, Hongyan, Engel, Christoph, de la Hoya, Miguel, Peterlongo, Paolo, Yannoukakos, Drakoulis, Livraghi, Luca, Radice, Paolo, Thomassen, Mads, Hansen, Thomas V. O., Gerdes, Anne-Marie, Nielsen, Henriette R., Caputo, Sandrine M., Zambelli, Alberto, Borg, Ake, Solano, Angela, Thomas, Abigail, Parsons, Michael T., Antoniou, Antonis C., Leslie, Goska, Yang, Xin, Chenevix-Trench, Georgia, Caldes, Trinidad, Kwong, Ava, Pedersen, Inge Sokilde, Lautrup, Charlotte K., John, Esther M., Terry, Mary Beth, Hopper, John L., Southey, Melissa C., Andrulis, Irene L., Tischkowitz, Marc, Janavicius, Ramunas, Boonen, Susanne E., Kroeldrup, Lone, Varesco, Liliana, Hamann, Ute, Vega, Ana, Palmero, Edenir, I, Garber, Judy, Montagna, Marco, Van Asperen, Christi J., Foretova, Lenka, Greene, Mark H., Selkirk, Tina, Moller, Pal, Toland, Amanda E., Domchek, Susan M., James, Paul A., Thorne, Heather, Eccles, Diana M., Nielsen, Sarah M., Manoukian, Siranoush, Pasini, Barbara, Caligo, Maria A., Lazaro, Conxi, Kirk, Judy, Wappenschmidt, Barbara, Spurdle, Amanda B., Couch, Fergus J., Schmutzler, Rita, and Goldgar, David E.

Abstract

Purpose: Germline genetic testing for BRCA1 and BRCA2 variants has been a part of clinical practice for >2 decades. However, no studies have compared the cancer risks associated with missense pathogenic variants (PVs) with those associated with protein truncating (PTC) variants. Methods: We collected 582 informative pedigrees segregating 1 of 28 missense PVs in BRCA1 and 153 pedigrees segregating 1 of 12 missense PVs in BRCA2. We analyzed 324 pedigrees with PTC variants in BRCA1 and 214 pedigrees with PTC variants in BRCA2. Cancer risks were estimated using modified segregation analysis. Results: Estimated breast cancer risks were markedly lower for women aged >50 years carrying BRCA1 missense PVs than for the women carrying BRCA1 PTC variants (hazard ratio [HR] = 3.9 [2.4-6.2] for PVs vs 12.8 [5.7-28.7] for PTC variants; P =.01), particularly for missense PVs in the BRCA1 C-terminal domain (HR = 2.8 [1.4-5.6]; P =.005). In case of BRCA2, for women aged >50 years, the HR was 3.9 (2.0-7.2) for those heterozygous for missense PVs compared with 7.0 (3.3-14.7) for those harboring PTC variants. BRCA1 p.[Cys64Arg] and BRCA2 p.[Trp2626Cys] were associated with particularly low risks of breast cancer compared with other PVs. Conclusion: These results have important implications for the counseling of at-risk women who harbor missense PVs in the BRCA1/2 genes. (C) 2021 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.

Published
2022

46. SPiP:Splicing Prediction Pipeline, a machine learning tool for massive detection of exonic and intronic variant effects on mRNA splicing

Author

Leman, Raphaël, Parfait, Béatrice, Vidaud, Dominique, Girodon, Emmanuelle, Pacot, Laurence, Le Gac, Gérald, Ka, Chandran, Ferec, Claude, Fichou, Yann, Quesnelle, Céline, Aucouturier, Camille, Muller, Etienne, Vaur, Dominique, Castera, Laurent, Boulouard, Flavie, Ricou, Agathe, Tubeuf, Hélène, Soukarieh, Omar, Gaildrat, Pascaline, Riant, Florence, Guillaud-Bataille, Marine, Caputo, Sandrine M., Caux-Moncoutier, Virginie, Boutry-Kryza, Nadia, Bonnet-Dorion, Françoise, Schultz, Ines, Rossing, Maria, Quenez, Olivier, Goldenberg, Louis, Harter, Valentin, Parsons, Michael T., Spurdle, Amanda B., Frébourg, Thierry, Martins, Alexandra, Houdayer, Claude, Krieger, Sophie, Leman, Raphaël, Parfait, Béatrice, Vidaud, Dominique, Girodon, Emmanuelle, Pacot, Laurence, Le Gac, Gérald, Ka, Chandran, Ferec, Claude, Fichou, Yann, Quesnelle, Céline, Aucouturier, Camille, Muller, Etienne, Vaur, Dominique, Castera, Laurent, Boulouard, Flavie, Ricou, Agathe, Tubeuf, Hélène, Soukarieh, Omar, Gaildrat, Pascaline, Riant, Florence, Guillaud-Bataille, Marine, Caputo, Sandrine M., Caux-Moncoutier, Virginie, Boutry-Kryza, Nadia, Bonnet-Dorion, Françoise, Schultz, Ines, Rossing, Maria, Quenez, Olivier, Goldenberg, Louis, Harter, Valentin, Parsons, Michael T., Spurdle, Amanda B., Frébourg, Thierry, Martins, Alexandra, Houdayer, Claude, and Krieger, Sophie

Abstract

Modeling splicing is essential for tackling the challenge of variant interpretation as each nucleotide variation can be pathogenic by affecting pre-mRNA splicing via disruption/creation of splicing motifs such as 5′/3′ splice sites, branch sites, or splicing regulatory elements. Unfortunately, most in silico tools focus on a specific type of splicing motif, which is why we developed the Splicing Prediction Pipeline (SPiP) to perform, in one single bioinformatic analysis based on a machine learning approach, a comprehensive assessment of the variant effect on different splicing motifs. We gathered a curated set of 4616 variants scattered all along the sequence of 227 genes, with their corresponding splicing studies. The Bayesian analysis provided us with the number of control variants, that is, variants without impact on splicing, to mimic the deluge of variants from high-throughput sequencing data. Results show that SPiP can deal with the diversity of splicing alterations, with 83.13% sensitivity and 99% specificity to detect spliceogenic variants. Overall performance as measured by area under the receiving operator curve was 0.986, better than SpliceAI and SQUIRLS (0.965 and 0.766) for the same data set. SPiP lends itself to a unique suite for comprehensive prediction of spliceogenicity in the genomic medicine era. SPiP is available at: https://sourceforge.net/projects/splicing-prediction-pipeline/.

Published
2022

47. Novel germline MET pathogenic variants in French patients with papillary renal cell carcinomas type I

Author

Sebai, Molka, primary, Tulasne, David, additional, Caputo, Sandrine M., additional, Verkarre, Virginie, additional, Fernandes, Marie, additional, Guérin, Célia, additional, Reinhart, Fanny, additional, Adams, Séverine, additional, Maugard, Christine, additional, Caron, Olivier, additional, Guillaud‐Bataille, Marine, additional, Berthet, Pascaline, additional, Bignon, Yves‐Jean, additional, Bressac‐de Paillerets, Brigitte, additional, Burnichon, Nelly, additional, Chiesa, Jean, additional, Giraud, Sophie, additional, Lejeune, Sophie, additional, Limacher, Jean‐Marc, additional, Pauw, Antoine, additional, Stoppa‐Lyonnet, Dominique, additional, Zattara‐Cannoni, Hélène, additional, Deveaux, Sophie, additional, Lidereau, Rosette, additional, Richard, Stéphane, additional, and Rouleau, Etienne, additional

Published
2022
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48. Association and Performance of Polygenic Risk Scores for Breast Cancer Among French Women Presenting or Not a Familial Predisposition to the Disease

Author

Jiao, Yue, primary, Truong, Thérèse, additional, Eon-Marchais, Séverine, additional, Mebirouk, Noura, additional, Caputo, Sandrine M., additional, Dondon, Marie-Gabrielle, additional, Karimi, Mojgan, additional, Le Gal, Dorothée, additional, Beauvallet, Juana, additional, Le Floch, Edith, additional, Dandine-Roulland, Claire, additional, Bacq-Daian, Delphine, additional, Olaso, Robert, additional, Albuisson, Juliette, additional, Audebert-Bellanger, Séverine, additional, Berthet, Pascaline, additional, Bonadona, Valérie, additional, Buecher, Bruno, additional, Caron, Olivier, additional, Cavaillé, Mathias, additional, Chiesa, Jean, additional, Colas, Chrystelle, additional, Collonge-Rame, Marie-Agnès, additional, Coupier, Isabelle, additional, Delnatte, Capucine, additional, De Pauw, Antoine, additional, Dreyfus, Hélène, additional, Fert-Ferrer, Sandra, additional, Gauthier-Villars, Marion, additional, Gesta, Paul, additional, Giraud, Sophie, additional, Gladieff, Laurence, additional, Golmard, Lisa, additional, Lasset, Christine, additional, Lejeune-Dumoulin, Sophie, additional, Léone, Mélanie, additional, Limacher, Jean-Marc, additional, Lortholary, Alain, additional, Luporsi, Elisabeth, additional, Mari, Véronique, additional, Maugard, Christine M., additional, Mortemousque, Isabelle, additional, Mouret-Fourme, Emmanuelle, additional, Nambot, Sophie, additional, Noguès, Catherine, additional, Popovici, Cornel, additional, Prieur, Fabienne, additional, Pujol, Pascal, additional, Sevenet, Nicolas, additional, Sobol, Hagay, additional, Toulas, Christine, additional, Uhrhammer, Nancy, additional, Vaur, Dominique, additional, Venat, Laurence, additional, Boland-Augé, Anne, additional, Guénel, Pascal, additional, Deleuze, Jean-François, additional, Stoppa-Lyonnet, Dominique, additional, Andrieu, Nadine, additional, and Lesueur, Fabienne, additional

Published
2022
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49. BRCA1 Circos: a visualisation resource for functional analysis of missense variants

Author

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, Santamariña Pena, Marta, 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
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