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

KConFab Investigators

doi:10.1002/humu.23818

Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants

Standard

Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants : An ENIGMA resource to support clinical variant classification. / KConFab Investigators.

in: HUM MUTAT, Jahrgang 40, Nr. 9, 09.2019, S. 1557-1578.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

KConFab Investigators 2019, 'Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification', HUM MUTAT, Jg. 40, Nr. 9, S. 1557-1578. https://doi.org/10.1002/humu.23818

APA

KConFab Investigators (2019). Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification. HUM MUTAT, 40(9), 1557-1578. https://doi.org/10.1002/humu.23818

Vancouver

KConFab Investigators. Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification. HUM MUTAT. 2019 Sep;40(9):1557-1578. https://doi.org/10.1002/humu.23818

Bibtex

@article{dcb02b6c1d9c44cfb60092567d4adad5,

title = "Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification",

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.",

keywords = "Alternative Splicing, BRCA1 Protein/genetics, BRCA2 Protein/genetics, Computational Biology/methods, Early Detection of Cancer, Female, Genetic Predisposition to Disease, Humans, Likelihood Functions, Male, Multifactorial Inheritance, Mutation, Missense, Neoplasms/diagnosis",

author = "Parsons, {Michael T} and Emma Tudini and Hongyan Li and Eric Hahnen and Barbara Wappenschmidt and Lidia Feliubadal{\'o} and Aalfs, {Cora M} and Simona Agata and Kristiina Aittom{\"a}ki and Elisa Alducci and Alonso-Cerezo, {Mar{\'i}a Concepci{\'o}n} and Norbert Arnold and Bernd Auber and Rachel Austin and Jacopo Azzollini and Judith Balma{\~n}a and Elena Barbieri and Bartram, {Claus R} and Ana Blanco and Britta Bl{\"u}mcke and Sandra Bonache and Bernardo Bonanni and {\AA}ke Borg and Beatrice Bortesi and Joan Brunet and Carla Bruzzone and Karolin Bucksch and Giulia Cagnoli and Trinidad Cald{\'e}s and Almuth Caliebe and Caligo, {Maria A} and Mariarosaria Calvello and Capone, {Gabriele L} and Caputo, {Sandrine M} and Ileana Carnevali and Estela Carrasco and Virginie Caux-Moncoutier and Pietro Cavalli and Giulia Cini and Clarke, {Edward M} and Paola Concolino and Cops, {Elisa J} and Laura Cortesi and Couch, {Fergus J} and Esther Darder and {de la Hoya}, Miguel and Michael Dean and Irmgard Debatin and {Del Valle}, Jes{\'u}s and Capucine Delnatte and Nicolas Derive and Orland Diez and Nina Ditsch and Domchek, {Susan M} and V{\'e}ronique Dutrannoy and Eccles, {Diana M} and Hans Ehrencrona and Ute Enders and Evans, {D Gareth} and Chantal Farra and Ulrike Faust and Ute Felbor and Irene Feroce and Miriam Fine and Foulkes, {William D} and Galvao, {Henrique C R} and Gaetana Gambino and Andrea Gehrig and Francesca Gensini and Anne-Marie Gerdes and Aldo Germani and Jutta Giesecke and Viviana Gismondi and Carolina G{\'o}mez and {G{\'o}mez Garcia}, {Encarna B} and Sara Gonz{\'a}lez and Elia Grau and Sabine Grill and Eva Gross and Aliana Guerrieri-Gonzaga and Marine Guillaud-Bataille and Sara Guti{\'e}rrez-Enr{\'i}quez and Thomas Haaf and Karl Hackmann and Hansen, {Thomas V O} and Marion Harris and Jan Hauke and Tilman Heinrich and Heide Hellebrand and Herold, {Karen N} and Ellen Honisch and Judit Horvath and Claude Houdayer and Verena H{\"u}bbel and Silvia Iglesias and Angel Izquierdo and James, {Paul A} and Janssen, {Linda A M} and Udo Jeschke and Silke Kaulfu{\ss} and Katharina Keupp and Marion Kiechle and Alexandra K{\"o}lbl and Sophie Krieger and Kruse, {Torben A} and Anders Kvist and Fiona Lalloo and Mirjam Larsen and Lattimore, {Vanessa L} and Charlotte Lautrup and Susanne Ledig and Elena Leinert and Lewis, {Alexandra L} and Joanna Lim and Markus Loeffler and Adri{\`a} L{\'o}pez-Fern{\'a}ndez and Emanuela Lucci-Cordisco and Nicolai Maass and Siranoush Manoukian and Monica Marabelli and Laura Matricardi and Alfons Meindl and Michelli, {Rodrigo D} and Setareh Moghadasi and Alejandro Moles-Fern{\'a}ndez and Marco Montagna and Gemma Montalban and Monteiro, {Alvaro N} and Eva Montes and Luigi Mori and Lidia Moserle and M{\"u}ller, {Clemens R} and Christoph Mundhenke and Nadia Naldi and Nathanson, {Katherine L} and Matilde Navarro and Heli Nevanlinna and Nichols, {Cassandra B} and Dieter Niederacher and Nielsen, {Henriette R} and Kai-Ren Ong and Nicholas Pachter and Palmero, {Edenir I} and Laura Papi and Pedersen, {Inge Sokilde} and Bernard Peissel and Pedro Perez-Segura and Katharina Pfeifer and Marta Pineda and Esther Pohl-Rescigno and Poplawski, {Nicola K} and Berardino Porfirio and Quante, {Anne S} and Juliane Ramser and Reis, {Rui M} and Fran{\c c}oise Revillion and Kerstin Rhiem and Barbara Riboli and Julia Ritter and Daniela Rivera and Paula Rofes and Andreas Rump and Monica Salinas and {S{\'a}nchez de Abajo}, {Ana Mar{\'i}a} and Gunnar Schmidt and Ulrike Schoenwiese and Jochen Seggewi{\ss} and Ares Solanes and Doris Steinemann and Mathias Stiller and Dominique Stoppa-Lyonnet and Sullivan, {Kelly J} and Rachel Susman and Christian Sutter and Tavtigian, {Sean V} and Teo, {Soo H} and Alex Teul{\'e} and Mads Thomassen and Tibiletti, {Maria Grazia} and Marc Tischkowitz and Silvia Tognazzo and Toland, {Amanda E} and Eva Tornero and Therese T{\"o}rngren and Sara Torres-Esquius and Angela Toss and Trainer, {Alison H} and Tucker, {Katherine M} and {van Asperen}, {Christi J} and {van Mackelenbergh}, {Marion T} and Liliana Varesco and Gardenia Vargas-Parra and Raymonda Varon and Ana Vega and {\'A}ngela Velasco and Anne-Sophie Vesper and Alessandra Viel and Vreeswijk, {Maaike P G} and Wagner, {Sebastian A} and Anke Waha and Walker, {Logan C} and Walters, {Rhiannon J} and Shan Wang-Gohrke and Weber, {Bernhard H F} and Wilko Weichert and Kerstin Wieland and Lisa Wiesm{\"u}ller and Isabell Witzel and Achim W{\"o}ckel and Woodward, {Emma R} and Silke Zachariae and Valentina Zampiga and Christine Zeder-G{\"o}{\ss} and Conxi L{\'a}zaro and {De Nicolo}, Arcangela and Paolo Radice and Christoph Engel and Schmutzler, {Rita K} and Goldgar, {David E} and Spurdle, {Amanda B} and {KConFab Investigators}",

note = "{\textcopyright} 2019 Wiley Periodicals, Inc.",

year = "2019",

month = sep,

doi = "10.1002/humu.23818",

language = "English",

volume = "40",

pages = "1557--1578",

journal = "HUM MUTAT",

issn = "1059-7794",

publisher = "Wiley-Liss Inc.",

number = "9",

}

RIS

TY - JOUR

T1 - Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants

T2 - An ENIGMA resource to support clinical variant classification

AU - Parsons, Michael T

AU - Tudini, Emma

AU - Li, Hongyan

AU - Hahnen, Eric

AU - Wappenschmidt, Barbara

AU - Feliubadaló, Lidia

AU - Aalfs, Cora M

AU - Agata, Simona

AU - Aittomäki, Kristiina

AU - Alducci, Elisa

AU - Alonso-Cerezo, María Concepción

AU - Arnold, Norbert

AU - Auber, Bernd

AU - Austin, Rachel

AU - Azzollini, Jacopo

AU - Balmaña, Judith

AU - Barbieri, Elena

AU - Bartram, Claus R

AU - Blanco, Ana

AU - Blümcke, Britta

AU - Bonache, Sandra

AU - Bonanni, Bernardo

AU - Borg, Åke

AU - Bortesi, Beatrice

AU - Brunet, Joan

AU - Bruzzone, Carla

AU - Bucksch, Karolin

AU - Cagnoli, Giulia

AU - Caldés, Trinidad

AU - Caliebe, Almuth

AU - Caligo, Maria A

AU - Calvello, Mariarosaria

AU - Capone, Gabriele L

AU - Caputo, Sandrine M

AU - Carnevali, Ileana

AU - Carrasco, Estela

AU - Caux-Moncoutier, Virginie

AU - Cavalli, Pietro

AU - Cini, Giulia

AU - Clarke, Edward M

AU - Concolino, Paola

AU - Cops, Elisa J

AU - Cortesi, Laura

AU - Couch, Fergus J

AU - Darder, Esther

AU - de la Hoya, Miguel

AU - Dean, Michael

AU - Debatin, Irmgard

AU - Del Valle, Jesús

AU - Delnatte, Capucine

AU - Derive, Nicolas

AU - Diez, Orland

AU - Ditsch, Nina

AU - Domchek, Susan M

AU - Dutrannoy, Véronique

AU - Eccles, Diana M

AU - Ehrencrona, Hans

AU - Enders, Ute

AU - Evans, D Gareth

AU - Farra, Chantal

AU - Faust, Ulrike

AU - Felbor, Ute

AU - Feroce, Irene

AU - Fine, Miriam

AU - Foulkes, William D

AU - Galvao, Henrique C R

AU - Gambino, Gaetana

AU - Gehrig, Andrea

AU - Gensini, Francesca

AU - Gerdes, Anne-Marie

AU - Germani, Aldo

AU - Giesecke, Jutta

AU - Gismondi, Viviana

AU - Gómez, Carolina

AU - Gómez Garcia, Encarna B

AU - González, Sara

AU - Grau, Elia

AU - Grill, Sabine

AU - Gross, Eva

AU - Guerrieri-Gonzaga, Aliana

AU - Guillaud-Bataille, Marine

AU - Gutiérrez-Enríquez, Sara

AU - Haaf, Thomas

AU - Hackmann, Karl

AU - Hansen, Thomas V O

AU - Harris, Marion

AU - Hauke, Jan

AU - Heinrich, Tilman

AU - Hellebrand, Heide

AU - Herold, Karen N

AU - Honisch, Ellen

AU - Horvath, Judit

AU - Houdayer, Claude

AU - Hübbel, Verena

AU - Iglesias, Silvia

AU - Izquierdo, Angel

AU - James, Paul A

AU - Janssen, Linda A M

AU - Jeschke, Udo

AU - Kaulfuß, Silke

AU - Keupp, Katharina

AU - Kiechle, Marion

AU - Kölbl, Alexandra

AU - Krieger, Sophie

AU - Kruse, Torben A

AU - Kvist, Anders

AU - Lalloo, Fiona

AU - Larsen, Mirjam

AU - Lattimore, Vanessa L

AU - Lautrup, Charlotte

AU - Ledig, Susanne

AU - Leinert, Elena

AU - Lewis, Alexandra L

AU - Lim, Joanna

AU - Loeffler, Markus

AU - López-Fernández, Adrià

AU - Lucci-Cordisco, Emanuela

AU - Maass, Nicolai

AU - Manoukian, Siranoush

AU - Marabelli, Monica

AU - Matricardi, Laura

AU - Meindl, Alfons

AU - Michelli, Rodrigo D

AU - Moghadasi, Setareh

AU - Moles-Fernández, Alejandro

AU - Montagna, Marco

AU - Montalban, Gemma

AU - Monteiro, Alvaro N

AU - Montes, Eva

AU - Mori, Luigi

AU - Moserle, Lidia

AU - Müller, Clemens R

AU - Mundhenke, Christoph

AU - Naldi, Nadia

AU - Nathanson, Katherine L

AU - Navarro, Matilde

AU - Nevanlinna, Heli

AU - Nichols, Cassandra B

AU - Niederacher, Dieter

AU - Nielsen, Henriette R

AU - Ong, Kai-Ren

AU - Pachter, Nicholas

AU - Palmero, Edenir I

AU - Papi, Laura

AU - Pedersen, Inge Sokilde

AU - Peissel, Bernard

AU - Perez-Segura, Pedro

AU - Pfeifer, Katharina

AU - Pineda, Marta

AU - Pohl-Rescigno, Esther

AU - Poplawski, Nicola K

AU - Porfirio, Berardino

AU - Quante, Anne S

AU - Ramser, Juliane

AU - Reis, Rui M

AU - Revillion, Françoise

AU - Rhiem, Kerstin

AU - Riboli, Barbara

AU - Ritter, Julia

AU - Rivera, Daniela

AU - Rofes, Paula

AU - Rump, Andreas

AU - Salinas, Monica

AU - Sánchez de Abajo, Ana María

AU - Schmidt, Gunnar

AU - Schoenwiese, Ulrike

AU - Seggewiß, Jochen

AU - Solanes, Ares

AU - Steinemann, Doris

AU - Stiller, Mathias

AU - Stoppa-Lyonnet, Dominique

AU - Sullivan, Kelly J

AU - Susman, Rachel

AU - Sutter, Christian

AU - Tavtigian, Sean V

AU - Teo, Soo H

AU - Teulé, Alex

AU - Thomassen, Mads

AU - Tibiletti, Maria Grazia

AU - Tischkowitz, Marc

AU - Tognazzo, Silvia

AU - Toland, Amanda E

AU - Tornero, Eva

AU - Törngren, Therese

AU - Torres-Esquius, Sara

AU - Toss, Angela

AU - Trainer, Alison H

AU - Tucker, Katherine M

AU - van Asperen, Christi J

AU - van Mackelenbergh, Marion T

AU - Varesco, Liliana

AU - Vargas-Parra, Gardenia

AU - Varon, Raymonda

AU - Vega, Ana

AU - Velasco, Ángela

AU - Vesper, Anne-Sophie

AU - Viel, Alessandra

AU - Vreeswijk, Maaike P G

AU - Wagner, Sebastian A

AU - Waha, Anke

AU - Walker, Logan C

AU - Walters, Rhiannon J

AU - Wang-Gohrke, Shan

AU - Weber, Bernhard H F

AU - Weichert, Wilko

AU - Wieland, Kerstin

AU - Wiesmüller, Lisa

AU - Witzel, Isabell

AU - Wöckel, Achim

AU - Woodward, Emma R

AU - Zachariae, Silke

AU - Zampiga, Valentina

AU - Zeder-Göß, Christine

AU - Lázaro, Conxi

AU - De Nicolo, Arcangela

AU - Radice, Paolo

AU - Engel, Christoph

AU - Schmutzler, Rita K

AU - Goldgar, David E

AU - Spurdle, Amanda B

AU - KConFab Investigators

PY - 2019/9

Y1 - 2019/9

N2 - 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.

AB - 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.

KW - Alternative Splicing

KW - BRCA1 Protein/genetics

KW - BRCA2 Protein/genetics

KW - Computational Biology/methods

KW - Early Detection of Cancer

KW - Female

KW - Genetic Predisposition to Disease

KW - Humans

KW - Likelihood Functions

KW - Male

KW - Multifactorial Inheritance

KW - Mutation, Missense

KW - Neoplasms/diagnosis

U2 - 10.1002/humu.23818

DO - 10.1002/humu.23818

M3 - SCORING: Journal article

C2 - 31131967

VL - 40

SP - 1557

EP - 1578

JO - HUM MUTAT

JF - HUM MUTAT

SN - 1059-7794

IS - 9

ER -