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1. Male with an apparently normal phenotype carrying a BRCA1 exon 20 duplication in trans to a BRCA1 frameshift variant

Author

Ines Block, Àngels Mateu-Regué, Thi Tuyet Nhu Do, Ieva Miceikaite, Daniel Sdogati, Martin J. Larsen, Qin Hao, Henriette Roed Nielsen, Susanne E. Boonen, Anne-Bine Skytte, Uffe Birk Jensen, Louise K. Høffding, Arcangela De Nicolo, Alessandra Viel, Emma Tudini, Michael T. Parsons, Thomas V. O. Hansen, Maria Rossing, Torben A. Kruse, Amanda B. Spurdle, and Mads Thomassen

Subjects
BRCA1, Dual carrier, Fanconi Anemia, Variant classification, Exon duplication, Transcription activation domain assay, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Reports of dual carriers of pathogenic BRCA1 variants in trans are extremely rare, and so far, most individuals have been associated with a Fanconi Anemia-like phenotype. Methods We identified two families with a BRCA1 in-frame exon 20 duplication (Ex20dup). In one male individual, the variant was in trans with the BRCA1 frameshift variant c.2475delC p.(Asp825Glufs*21). We performed splicing analysis and used a transcription activation domain (TAD) assay to assess the functional impact of Ex20dup. We collected pedigrees and mapped the breakpoints of the duplication by long- and short-read genome sequencing. In addition, we performed a mitomycin C (MMC) assay from the dual carrier using cultured lymphoblastoid cells. Results Genome sequencing and RNA analysis revealed the BRCA1 exon 20 duplication to be in tandem. The duplication was expressed without skipping any one of the two exon 20 copies, resulting in a lack of wild-type transcripts from this allele. TAD assay indicated that the Ex20dup variant has a functional level similar to the well-known moderate penetrant pathogenic BRCA1 variant c.5096G > A p.(Arg1699Gln). MMC assay of the dual carrier indicated a slightly impaired chromosomal repair ability. Conclusions This is the first reported case where two BRCA1 variants with demonstrated functional impact are identified in trans in a male patient with an apparently normal clinical phenotype and no BRCA1-associated cancer. The results pinpoint a minimum necessary BRCA1 protein activity to avoid a Fanconi Anemia-like phenotype in compound heterozygous status and yet still predispose carriers to hormone-related cancers. These findings urge caution when counseling families regarding potential Fanconi Anemia risk. Furthermore, prudence should be taken when classifying individual variants as benign based on co-occurrence in trans with well-established pathogenic variants.

Published
2024
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2. The clinical utility and costs of whole-genome sequencing to detect cancer susceptibility variants—a multi-site prospective cohort study

Author

Aimee L. Davidson, Uwe Dressel, Sarah Norris, Daffodil M. Canson, Dylan M. Glubb, Cristina Fortuno, Georgina E. Hollway, Michael T. Parsons, Miranda E. Vidgen, Oliver Holmes, Lambros T. Koufariotis, Vanessa Lakis, Conrad Leonard, Scott Wood, Qinying Xu, Amy E. McCart Reed, Hilda A. Pickett, Mohammad K. Al-Shinnag, Rachel L. Austin, Jo Burke, Elisa J. Cops, Cassandra B. Nichols, Annabel Goodwin, Marion T. Harris, Megan J. Higgins, Emilia L. Ip, Catherine Kiraly-Borri, Chiyan Lau, Julia L. Mansour, Michael W. Millward, Melissa J. Monnik, Nicholas S. Pachter, Abiramy Ragunathan, Rachel D. Susman, Sharron L. Townshend, Alison H. Trainer, Simon L. Troth, Katherine M. Tucker, Mathew J. Wallis, Maie Walsh, Rachel A. Williams, Ingrid M. Winship, Felicity Newell, Emma Tudini, John V. Pearson, Nicola K. Poplawski, Helen G. Mar Fan, Paul A. James, Amanda B. Spurdle, Nicola Waddell, and Robyn L. Ward

Subjects
Familial cancer, Genetics, Variants, Whole-genome sequencing, Diagnostic testing, Health economics, Medicine, QH426-470
Abstract

Abstract Background Many families and individuals do not meet criteria for a known hereditary cancer syndrome but display unusual clusters of cancers. These families may carry pathogenic variants in cancer predisposition genes and be at higher risk for developing cancer. Methods This multi-centre prospective study recruited 195 cancer-affected participants suspected to have a hereditary cancer syndrome for whom previous clinical targeted genetic testing was either not informative or not available. To identify pathogenic disease-causing variants explaining participant presentation, germline whole-genome sequencing (WGS) and a comprehensive cancer virtual gene panel analysis were undertaken. Results Pathogenic variants consistent with the presenting cancer(s) were identified in 5.1% (10/195) of participants and pathogenic variants considered secondary findings with potential risk management implications were identified in another 9.7% (19/195) of participants. Health economic analysis estimated the marginal cost per case with an actionable variant was significantly lower for upfront WGS with virtual panel ($8744AUD) compared to standard testing followed by WGS ($24,894AUD). Financial analysis suggests that national adoption of diagnostic WGS testing would require a ninefold increase in government annual expenditure compared to conventional testing. Conclusions These findings make a case for replacing conventional testing with WGS to deliver clinically important benefits for cancer patients and families. The uptake of such an approach will depend on the perspectives of different payers on affordability.

Published
2023
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3. P076: The ClinGen ENIGMA BRCA1/2 expert panel: A dynamic framework for evidence-based recommendations to improve classification criteria for variants in BRCA1/2

Author

Michael Parsons, Michael Anderson, Windy Berkofsky-Fessler, Sandrine Caputo, Raymond Chan, Melissa Cline, Fergus Couch, Miguel de la Hoya, Bing-Jian Feng, David Goldgar, Encarna Gomez-Garcia, Susan Hiraki, Megan Holdren, Claude Houdayer, Paul James, Rachid Karam, Huei San Leong, Alexandra Martins, Arjen Mensenkamp, Alvaro Monteiro, Vaishnavi Nathan, Robert O'Connor, Tina Pesaran, Paolo Radice, Marcy Richardson, Gunnar Schmidt, Inge Sokilde Pedersen, Melissa Southey, Sean Tavtigian, Bryony Thompson, Amanda Toland, Emma Tudini, Clare Turnbull, Maaike Vreeswijk, Logan Walker, Lauren Zec, and Amanda Spurdle

Subjects
Genetics, QH426-470, Medicine
Published
2023
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5. Australian Genomics: Outcomes of a 5-year national program to accelerate the integration of genomics in healthcare

Author

Zornitza Stark, Tiffany Boughtwood, Matilda Haas, Jeffrey Braithwaite, Clara L. Gaff, Ilias Goranitis, Amanda B. Spurdle, David P. Hansen, Oliver Hofmann, Nigel Laing, Sylvia Metcalfe, Ainsley J. Newson, Hamish S. Scott, Natalie Thorne, Robyn L. Ward, Marcel E. Dinger, Stephanie Best, Janet C. Long, Sean M. Grimmond, John Pearson, Nicola Waddell, Christopher P. Barnett, Matthew Cook, Michael Field, David Fielding, Stephen B. Fox, Jozef Gecz, Adam Jaffe, Richard J. Leventer, Paul J. Lockhart, Sebastian Lunke, Andrew J. Mallett, Julie McGaughran, Linda Mileshkin, Katia Nones, Tony Roscioli, Ingrid E. Scheffer, Christopher Semsarian, Cas Simons, David M. Thomas, David R. Thorburn, Richard Tothill, Deborah White, Sally Dunwoodie, Peter T. Simpson, Peta Phillips, Marie-Jo Brion, Keri Finlay, Michael CJ. Quinn, Tessa Mattiske, Emma Tudini, Kirsten Boggs, Sean Murray, Kathy Wells, John Cannings, Andrew H. Sinclair, John Christodoulou, Kathryn N. North, Stark, Zornitza, Boughtwood, Tiffany, Haas, Matilda, Braithwaite, Jeffrey, Scott, Hamish S, and North, Kathryn N

Subjects
Genetics, Genetics (clinical)
Abstract

Refereed/Peer-reviewed Australian Genomics is a national collaborative partnership of more than 100 organizations piloting a whole-of-system approach to integrating genomics into healthcare, based on federation principles. In the first five years of operation, Australian Genomics has evaluated the outcomes of genomic testing in more than 5,200 individuals across 19 rare disease and cancer flagship studies. Comprehensive analyses of the health economic, policy, ethical, legal, implementation and workforce implications of incorporating genomics in the Australian context have informed evidence-based change in policy and practice, resulting in national government funding and equity of access for a range of genomic tests. Simultaneously, Australian Genomics has built national skills, infrastructure, policy, and data resources to enable effective data sharing to drive discovery research and support improvements in clinical genomic delivery.

Published
2023

6. Catastrophic chemotherapy toxicity leading to diagnosis of Fanconi anaemia due to FANCD1/BRCA2 during adulthood: description of an emerging phenotype

Author

Amanda B. Spurdle, Rodney J. Scott, Catriona M. McNeil, Emilia Ip, Charbel Sandroussi, Annabel Goodwin, Tahlia Scheinberg, Christina Brown, Pascale Guitera, Gladys Ho, Emma Tudini, and Peter Grimison

Subjects
Pediatrics, medicine.medical_specialty, Chemotherapy, medicine.diagnostic_test, business.industry, medicine.medical_treatment, Cancer, medicine.disease, hemic and lymphatic diseases, Primary Ovarian Failure, Genetics, medicine, Adenocarcinoma, Gastrointestinal cancer, Family history, Ovarian cancer, business, Genetics (clinical), Genetic testing
Abstract

Fanconi anaemia due to biallelic loss of BRCA2 (Fanconi anaemia subtype D1) is traditionally diagnosed during childhood with cancer rates historically reported as 97% by 5.2 years. This report describes an adult woman with a history of primary ovarian failure, who was diagnosed with gastrointestinal adenocarcinoma and BRCA2-associated Fanconi anaemia at 23 years of age, only after she suffered severe chemotherapy toxicity. The diagnostic challenges include atypical presentation, initial false-negative chromosome fragility testing and variant classification. It highlights gastrointestinal adenocarcinoma as a consideration for adults with biallelic BRCA2 pathogenic variants with implications for surveillance. After over 4 years, the patient has no evidence of gastrointestinal cancer recurrence although the tumour was initially considered only borderline resectable. The use of platinum-based chemotherapy, to which heterozygous BRCA2 carriers are known to respond, may have had a beneficial anticancer effect, but caution is advised given its extreme immediate toxicity at standard dosing. Fanconi anaemia should be considered as a cause for women with primary ovarian failure of unknown cause and referral to cancer genetic services recommended when there is a family history of cancer in the hereditary breast/ovarian cancer spectrum.

Published
2021

7. Reporting clinically relevant genetic variants unrelated to genomic test requests: a survey of Australian clinical laboratory policies and practices

Author

Emma Tudini, Matilda A Haas, Tessa Mattiske, and Amanda B Spurdle

Subjects
Genetics, Genetics (clinical)
Abstract

Approaches to reporting clinically important genetic findings unrelated to the initial test request vary internationally. We sought to investigate practices regarding the management and return of these findings in Australia. Australian clinically accredited genetic testing laboratories were surveyed in 2017 and 2020 regarding their opinions on issues relating to the return of clinically important genetic findings unrelated to the initial test request. Responses were collated and analysed for 15 laboratories in 2017, and 17 laboratories in 2020. Content analysis was also performed on seven laboratory policies in 2020. Analysis showed that overall there was a lack of consensus about the terminology used to describe such findings and reporting practices across different testing contexts. A clear exception was that no laboratories were actively searching for a list of medically actionable genes (eg, American College of Medical Genetics and Genomics secondary findings gene list). Laboratory policies showed little consistency in the documentation of issues related to the handling of these findings. These findings indicate a need for Australian-specific policy guidance that covers all aspects of clinically important genetic findings unrelated to the initial test request. We present recommendations for consideration when developing laboratory policies.

Published
2022

8. Analysis of hereditary cancer gene variant classifications from ClinVar indicates a need for regular reassessment of clinical assertions

Author

Aimee L. Davidson, Olga Kondrashova, Conrad Leonard, Scott Wood, Emma Tudini, Georgina E. Hollway, John V. Pearson, Felicity Newell, Amanda B. Spurdle, and Nicola Waddell

Subjects
Genetics, Genetics (clinical)
Abstract

The clinical classification of variants may change with new information, however, there is limited guidance on how often significant changes in variant classification occur. We used ClinVar to examine how variant classification changes over time. We developed a custom parser and accessed variant data from ClinVar between January 2015 and July 2021. The ClinVar-assigned "aggregate" classification of variants in 121 hereditary cancer genes was harmonized across releases to align to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology terms. Aggregate classification categories were grouped as: benign/likely benign (B/LB); likely pathogenic/pathogenic (LP/P); variant of uncertain significance (VUS); conflicting interpretations of pathogenicity (Conflicting); or Other. We profiled changes in aggregate variant classification between consecutive semi-annual ClinVar releases. The proportion of variants that changed aggregate classification between semi-annual ClinVar releases ranged from 0.6% to 6.4%. The most frequent changes were "VUS to conflicting," "other to LP/P," and "B/LB to Conflicting." A limited number of variants changed aggregate classification from "LP/P to B/LB," or vice versa. Our analysis indicates need for regular reassessment of clinical variant interpretations. The parser developed for this project will facilitate extraction of relevant interpretation data from ClinVar.

Published
2022

9. Shariant platform: Enabling evidence sharing across Australian clinical genetic-testing laboratories to support variant interpretation

Author

Emma Tudini, James Andrews, David M. Lawrence, Sarah L. King-Smith, Naomi Baker, Leanne Baxter, John Beilby, Bruce Bennetts, Victoria Beshay, Michael Black, Tiffany F. Boughtwood, Kristian Brion, Pak Leng Cheong, Michael Christie, John Christodoulou, Belinda Chong, Kathy Cox, Mark R. Davis, Lucas Dejong, Marcel E. Dinger, Kenneth D. Doig, Evelyn Douglas, Andrew Dubowsky, Melissa Ellul, Andrew Fellowes, Katrina Fisk, Cristina Fortuno, Kathryn Friend, Renee L. Gallagher, Song Gao, Emma Hackett, Johanna Hadler, Michael Hipwell, Gladys Ho, Georgina Hollway, Amanda J. Hooper, Karin S. Kassahn, Rahul Krishnaraj, Chiyan Lau, Huong Le, Huei San Leong, Ben Lundie, Sebastian Lunke, Anthony Marty, Mary McPhillips, Lan T. Nguyen, Katia Nones, Kristen Palmer, John V. Pearson, Michael C.J. Quinn, Lesley H. Rawlings, Simon Sadedin, Louisa Sanchez, Andreas W. Schreiber, Emanouil Sigalas, Aygul Simsek, Julien Soubrier, Zornitza Stark, Bryony A. Thompson, James U, Cassandra G. Vakulin, Amanda V. Wells, Cheryl A. Wise, Rick Woods, Andrew Ziolkowski, Marie-Jo Brion, Hamish S. Scott, Natalie P. Thorne, Amanda B. Spurdle, Lauren Akesson, Richard Allcock, Katie Ashton, Damon A. Bell, Anna Brown, Michael Buckley, John R. Burnett, Linda Burrows, Alicia Byrne, Eva Chan, Corrina Cliffe, Roderick Clifton-Bligh, Susan Dooley, Miriam Fanjul Fernandez, Elizabeth Farnsworth, Thuong Ha, Denae Henry, Duncan Holds, Katherine Holman, Matilda Jackson, Sinlay Kang, Catherine Luxford, Sam McManus, Rachael Mehrtens, Cliff Meldrum, David Mossman, Sarah-Jane Pantaleo, Dean Phelan, Electra Pontikinas, Anja Ravine, Tony Roscioli, Rodney Scott, Keryn Simons, Oliver Vanwageningen, Tudini, Emma, Andrews, James, Lawrence, David M., King-Smith, Sarah L., Schreiber, Andreas W, James, U, and Shariant Consortium

Subjects
genomic variant, variant interpretations, Databases, Genetic, Technology Review, Genetics, Australia, Humans, Genetic Variation, Genetic Testing, Laboratories, Genetics (clinical), Australian laboratories
Abstract

Sharing genomic variant interpretations across laboratories promotes consistency in variant assertions. A landscape analysis of Australian clinical genetic-testing laboratories in 2017 identified that, despite the national-accreditation-body recommendations encouraging laboratories to submit genotypic data to clinical databases, fewer than 300 variants had been shared to the ClinVar public database. Consultations with Australian laboratories identified resource constraints limiting routine application of manual processes, consent issues, and differences in interpretation systems as barriers to sharing. This information was used to define key needs and solutions required to enable national sharing of variant interpretations. The Shariant platform, using both the GRCh37 and GRCh38 genome builds, was developed to enable ongoing sharing of variant interpretations and associated evidence between Australian clinical genetic-testing laboratories. Where possible, two-way automated sharing was implemented so that disruption to laboratory workflows would be minimized. Terms of use were developed through consultation and currently restrict access to Australian clinical genetic-testing laboratories. Shariant was designed to store and compare structured evidence, to promote and record resolution of inter-laboratory classification discrepancies, and to streamline the submission of variant assertions to ClinVar. As of December 2021, more than 14,000 largely prospectively curated variant records from 11 participating laboratories have been shared. Discrepant classifications have been identified for 11% (28/260) of variants submitted by more than one laboratory. We have demonstrated that co-design with clinical laboratories is vital to developing and implementing a national variant-interpretation sharing effort. This approach has improved inter-laboratory concordance and enabled opportunities to standardize interpretation practices.

Published
2022

10. Implementing gene curation for hereditary cancer susceptibility in Australia: achieving consensus on genes with clinical utility

Author

Yoland Antill, Paul A. James, Judy Kirk, Uwe Dressel, Nicola K. Poplawski, Lucinda Salmon, Nicholas Pachter, Aimee L Davidson, Sharron Townshend, Michael Gattas, Emma Tudini, Gillian Mitchell, Helen Mar Fan, Rachel Susman, Katherine M. Tucker, Robyn L. Ward, Michael Field, Ashley Crook, Alison H. Trainer, Amanda B. Spurdle, Lesley Andrews, and Rebecca Harris

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, Consensus, Genetic counseling, Genetic Counseling, Context (language use), Medical Oncology, 03 medical and health sciences, Strength of evidence, 0302 clinical medicine, Neoplasms, Genetics, Humans, Medicine, Genetic Predisposition to Disease, Genetic Testing, Gene, Genetic Association Studies, Germ-Line Mutation, Genetics (clinical), Genetic testing, Family Health, Genetics & Heredity, medicine.diagnostic_test, business.industry, Tumor Suppressor Proteins, Australia, Cancer, Molecular Sequence Annotation, medicine.disease, Penetrance, Pedigree, 030104 developmental biology, 030220 oncology & carcinogenesis, Family medicine, 06 Biological Sciences, 11 Medical and Health Sciences, Female, Hereditary Cancer, business
Abstract

BackgroundThe strength of evidence supporting the validity of gene-disease relationships is variable. Hereditary cancer has the additional complexity of low or moderate penetrance for some confirmed disease-associated alleles.MethodsTo promote national consistency in interpretation of hereditary cancer/tumour gene test results, we requested opinions of representatives from Australian Family Cancer Clinics regarding the clinical utility of 157 genes initially collated for a national research project. Viewpoints were sought by initial survey, face-to-face workshop and follow-up survey. Subsequent review was undertaken by the eviQ Cancer Genetics Reference Committee, a national resource providing evidence-based and consensus-driven cancer treatment protocols.ResultsGenes were categorised by clinical actionability as: relevant for testing on presentation of common cancer/tumour types (n=45); relevant for testing in the context of specific rare phenotypes (n=74); insufficient clinical utility (n=34) or contentious clinical utility (n=3). Opinions for several genes altered during the study time frame, due to new information.ConclusionThrough an iterative process, consensus was achieved on genes with clinical utility for hereditary cancer/tumour conditions in the Australian setting. This study highlighted need for regular review of gene-disease lists, a role assumed in Australia for hereditary cancer/tumour predisposition genes by the eviQ Cancer Genetics Reference Committee.

Published
2020

11. Standardized practices for RNA diagnostics using clinically accessible specimens reclassifies 75% of putative splicing variants

Author

Adam M. Bournazos, Lisa G. Riley, Shobhana Bommireddipalli, Lesley Ades, Lauren S. Akesson, Mohammad Al-Shinnag, Stephen I. Alexander, Alison D. Archibald, Shanti Balasubramaniam, Yemima Berman, Victoria Beshay, Kirsten Boggs, Jasmina Bojadzieva, Natasha J. Brown, Samantha J. Bryen, Michael F. Buckley, Belinda Chong, Mark R. Davis, Ruebena Dawes, Martin Delatycki, Liz Donaldson, Lilian Downie, Caitlin Edwards, Matthew Edwards, Amanda Engel, Lisa J. Ewans, Fathimath Faiz, Andrew Fennell, Michael Field, Mary-Louise Freckmann, Lyndon Gallacher, Russell Gear, Himanshu Goel, Shuxiang Goh, Linda Goodwin, Bernadette Hanna, James Harraway, Megan Higgins, Gladys Ho, Bruce K. Hopper, Ari E. Horton, Matthew F. Hunter, Aamira J. Huq, Sarah Josephi-Taylor, Himanshu Joshi, Edwin Kirk, Emma Krzesinski, Kishore R. Kumar, Frances Lemckert, Richard J. Leventer, Suzanna E. Lindsey-Temple, Sebastian Lunke, Alan Ma, Steven Macaskill, Amali Mallawaarachchi, Melanie Marty, Justine E. Marum, Hugh J. McCarthy, Manoj P. Menezes, Alison McLean, Di Milnes, Shekeeb Mohammad, David Mowat, Aram Niaz, Elizabeth E. Palmer, Chirag Patel, Shilpan G. Patel, Dean Phelan, Jason R. Pinner, Sulekha Rajagopalan, Matthew Regan, Jonathan Rodgers, Miriam Rodrigues, Richard H. Roxburgh, Rani Sachdev, Tony Roscioli, Ruvishani Samarasekera, Sarah A. Sandaradura, Elena Savva, Tim Schindler, Margit Shah, Ingrid B. Sinnerbrink, Janine M. Smith, Richard J. Smith, Amanda Springer, Zornitza Stark, Samuel P. Strom, Carolyn M. Sue, Kenneth Tan, Tiong Y. Tan, Esther Tantsis, Michel C. Tchan, Bryony A. Thompson, Alison H. Trainer, Karin van Spaendonck-Zwarts, Rebecca Walsh, Linda Warwick, Stephanie White, Susan M. White, Mark G. Williams, Meredith J. Wilson, Wui Kwan Wong, Dale C. Wright, Patrick Yap, Alison Yeung, Helen Young, Kristi J. Jones, Bruce Bennetts, Sandra T. Cooper, Ghusoon Abdulrasool, Ghamdan Al Eryani, Peer Arts, Richard Bagnall, Naomi L. Baker, Christopher Barnett, Sarah Beecroft, Marina Berbic, Michael Black, Jim Blackburn, Piers Blombery, Susan Branford, Jimmy Breen, Leslie Burnett, Daffodil Canson, Pak Cheong, Edward Chew, John Christodoulou, Seo-Kyung Chung, Mike Clark, Corrina Cliffe, Melissa Cole, Felicity Collins, Alison Compton, Antony Cooper, Mark Corbett, Mark Cowley, Tracy Dudding, Stefanie Eggers, Eduardo Eyras, Miriam Fanjul Fernandez, Andrew Fellowes, Ron Fleischer, Chiara Folland, Lucy Fox, Clara Gaff, Melanie Galea, Roula Ghaoui, Ilias Gornanitis, Thuong Ha, Rippei Hayashi, Ian Hayes, Alex Henderson, Luke Hesson, Erin Heyer, Michael Hildebrand, Michael Hipwell, Cass Hoskins, Matilda Jackson, Paul James, Justin Jong-Leong Wong, Karin Kassahn, Peter Kaub, Lucy Kevin, Smitha Kumble, Sarah Kummerfeld, Nigel Laing, Chiyan Lau, Eric Lee, Sarah Leighton, Ben Lundie, Chelsea Mayoh, Julie McGaughran, Mary McPhillips, Cliff Meldrum, Edwina Middleton, Kym Mina, Amy Nisselle, Emily Oates, Alicia Oshlack, Gayathri Parasivam, Michael Parsons, Michael Quinn, John Rasko, Gina Ravenscroft, Anja Ravine, Krista Recsei, Jacqueline Rehn, Stephen Robertson, Anne Ronan, Georgina Ryland, Simon Sadedin, Andreas Schreiber, Hamish Scott, Rodney Scott, Christopher Semsarian, Cas Simons, Emma Singer, Renee Smyth, Amanda Spurdle, Patricia Sullivan, Samantha Sundercombe, David Thorburn, John Toubia, Ronald Trent, Emma Tudini, Irina Voneague, Leigh Waddell, Logan Walker, Mathew Wallis, Nick Warnock, Robert Weatheritt, Deborah White, Ingrid Winship, Lisa Worgan, Kathy Wu, Andrew Ziolowski, Bournazos, Adam M, Riley, Lisa G, Bommireddipalli, Shobhana, Ades, Lesley, Cooper, Sandra T, Toubia, John, and Australasian Consortium for RNA Diagnostics

Subjects
Adult, Adolescent, RNA Splicing, Genetic counseling, putative splice variant, Biology, law.invention, genetic diagnosis, law, Exome Sequencing, Biopsy, medicine, Humans, variant classification, Gene, Genetics (clinical), Polymerase chain reaction, Genetics, medicine.diagnostic_test, Sequence Analysis, RNA, noncoding variant, RNA, Heterozygote advantage, Amplicon, Child, Preschool, Mutation, RNA splicing, pre-mRNA splicing
Abstract

usc Refereed/Peer-reviewed Purpose: Genetic variants causing aberrant premessenger RNA splicing are increasingly being recognized as causal variants in genetic disorders. In this study, we devise standardized practices for polymerase chain reaction (PCR)-based RNA diagnostics using clinically accessible specimens (blood, fibroblasts, urothelia, biopsy). Methods: A total of 74 families with diverse monogenic conditions (31% prenatal-congenital onset, 47% early childhood, and 22% teenage-adult onset) were triaged into PCR-based RNA testing, with comparative RNA sequencing for 19 cases. Results: Informative RNA assay data were obtained for 96% of cases, enabling variant reclassification for 75% variants that can be used for genetic counseling (71%), to inform clinical care (32%) and prenatal counseling (41%). Variant-associated mis-splicing was highly reproducible for 28 cases with samples from ≥2 affected individuals or heterozygotes and 10 cases with ≥2 biospecimens. PCR amplicons encompassing another segregated heterozygous variant was vital for clinical interpretation of 22 of 79 variants to phase RNA splicing events and discern complete from partial mis-splicing. Conclusion: RNA diagnostics enabled provision of a genetic diagnosis for 64% of recruited cases. PCR-based RNA diagnostics has capacity to analyze 81.3% of clinically significant genes, with long amplicons providing an advantage over RNA sequencing to phase RNA splicing events. The Australasian Consortium for RNA Diagnostics (SpliceACORD) provide clinically-endorsed, standardized protocols and recommendations for interpreting RNA assay data.

Published
2022

12. Catastrophic chemotherapy toxicity leading to diagnosis of Fanconi anaemia due to

Author

Emilia, Ip, Catriona, McNeil, Peter, Grimison, Tahlia, Scheinberg, Emma, Tudini, Gladys, Ho, Rodney J, Scott, Christina, Brown, Charbel, Sandroussi, Pascale, Guitera, Amanda B, Spurdle, and Annabel, Goodwin

Subjects
BRCA2 Protein, Fanconi Anemia, Phenotype, Humans, Breast Neoplasms, Female, Genetic Predisposition to Disease, Adenocarcinoma
Abstract

Fanconi anaemia due to biallelic loss of

Published
2021

13. Contributors

Author

Ana Catarina Alves, Christina Anne Austin-Tse, Mafalda Bourbon, Marcelo A. Carvalho, Ozge Ceyhan-Birsoy, George S. Charames, Joana Rita Chora, Mara Colombo, Xavier de la Cruz, Johan T. den Dunnen, Niels de Wind, Orland Diez, Anna B.R. Elias, D Gareth Evans, Lidia Feliubadaló, Vanessa C. Fernandes, Ivo F.A.C. Fokkema, Cristina Fortuno, Alice Garrett, Paolo Gasparini, Giorgia Girotto, Anna González-Neira, Karen W. Gripp, Sara Gutiérrez-Enríquez, Steven M. Harrison, Miguel de la Hoya, Jodie Ingles, Renee Johnson, Jordan Lerner-Ellis, Harvey Levy, Conxi Lázaro, Heather Mason-Suares, Ana Margarida Medeiros, Jessica L. Mester, Alejandro Moles-Fernández, Alvaro N.A. Monteiro, Anna Morgan, Thales C. Nepomuceno, Rocío Núñez-Torres, Selen Özkan, Natàlia Padilla, Michael T. Parsons, Tina F. Pesaran, Marta Pineda, Paolo Radice, Farrah Rajabi, Ebony Richardson, Peter Sabatini, Stephanie Sacharow, Amanda Spurdle, Bryony A. Thompson, Emma Tudini, Clare Turnbull, Lisa M. Vincent, Michael F. Walsh, and Nicholas Watkins

Published
2021

14. Classification of genetic variants in hereditary cancer genes

Author

Emma Tudini, Lídia Feliubadaló, Marta Pineda, and Michael T. Parsons

Subjects
Genetics, Mechanism (biology), Genetic variants, Hereditary Cancer, Clinical case, Biology, Pathogenicity, Gene, Loss function, Associated phenotype
Abstract

Since most hereditary cancer genes are tumour suppressor genes, the mechanism of pathogenicity of their variants is the loss of function. This is the case of the 4 example variants included in this chapter. For each of the variants, the presentation of a hypothetical clinical case that support the gene test request is followed by the basic information of the gene, associated phenotype and detected variant. The pathogenicity assessment of each variant is organised according to the data types on which ACMG/AMP recommended criteria are based. If additional data not considered by the ACMG/AMP is available, it is also presented. Finally, a table summarizes the criteria met by the variant and a biological and clinical interpretation is provided.

Published
2021

15. Caution: Plasmid DNA topology affects luciferase assay reproducibility and outcomes

Author

Amanda B. Spurdle, Melissa A. Brown, Emma Tudini, Jan Sevcik, Phillip J. Whiley, and Lez J. Burke

Subjects
Reproducibility, Chemistry, BRCA1 Protein, Reproducibility of Results, Transfection, DNA, Molecular biology, General Biochemistry, Genetics and Molecular Biology, Plasmid dna, Cell culture, Genes, Reporter, Gene expression, Luminescent Measurements, MCF-7 Cells, Humans, Luciferase, Luciferases, Topology (chemistry), Biotechnology, Plasmids
Published
2019

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

Author

Luigi Mori, Sara González, Elia Grau, Dieter Niederacher, Alexandra C. Kölbl, Ares Solanes, Cassandra B. Nichols, Marine Guillaud-Bataille, Ulrike Schoenwiese, Katherine L. Nathanson, Alfons Meindl, Ellen Honisch, Hans Ehrencrona, Ute Enders, Anke Waha, Trinidad Caldés, Inge Søkilde Pedersen, Ana Blanco, Emma Tudini, Conxi Lázaro, Paolo Radice, Torben A Kruse, María Concepción Alonso-Cerezo, Chantal Farra, Shan Wang-Gohrke, Wilko Weichert, Heli Nevanlinna, Setareh Moghadasi, Bernd Auber, Carla Bruzzone, Aliana Guerrieri-Gonzaga, Sabine Grill, Raymonda Varon, Nicolas Derive, Ana Vega, Nicolai Maass, Åke Borg, Cora M. Aalfs, Nadia Naldi, Silvia Iglesias, Kai Ren Ong, Encarna B. Gomez Garcia, Karl Hackmann, Emma R. Woodward, Norbert Arnold, David E. Goldgar, Bernard Peissel, Karolin Bucksch, Berardino Porfirio, Françoise Révillion, Angel Izquierdo, Isabell Witzel, Sebastian Wagner, Silke Zachariae, Elisa Alducci, Mads Thomassen, Jesús del Valle, Valentina Zampiga, Kerstin Rhiem, Lidia Moserle, Edenir Inêz Palmero, Maaike P.G. Vreeswijk, Christoph Mundhenke, Laura Papi, Alejandro Moles-Fernández, Paula Rofes, Ulrike Faust, Andrea Gehrig, Sandrine M. Caputo, Logan C. Walker, Fiona Lalloo, Ute Felbor, Joan Brunet, Henriette Roed Nielsen, Sean V. Tavtigian, Beatrice Bortesi, Thomas Hansen, Maria Grazia Tibiletti, Estela Carrasco, Lisa Wiesmüller, Viviana Gismondi, Sophie Krieger, Pedro Pérez-Segura, Esther Pohl-Rescigno, Emanuela Lucci-Cordisco, Barbara Wappenschmidt, Rui Manuel Reis, Gabriele Lorenzo Capone, Ileana Carnevali, Christi J. van Asperen, KCon Fab Investigators, Jochen Seggewiß, Rhiannon J. Walters, Irmgard Debatin, Susan M. Domchek, Marco Montagna, Francesca Gensini, Kristiina Aittomäki, Véronique Dutrannoy, Arcangela De Nicolo, Giulia Cagnoli, Elisa J. Cops, Henrique de Campos Reis Galvão, Giulia Cini, Barbara Riboli, Eva Tornero, Paul A. James, Judith Balmaña, Anne-Marie Gerdes, Heide Hellebrand, Miriam Fine, Mathias Stiller, Aldo Germani, Diana Eccles, Britta Blümcke, Dominique Stoppa-Lyonnet, Elena Leinert, Alexandra Lewis, Daniela Rivera, Verena Hübbel, Fergus J. Couch, Gunnar Schmidt, Katharina Keupp, Bernhard H. F. Weber, Tilman Heinrich, Mariarosaria Calvello, Michael Dean, Udo Jeschke, Vanessa Lattimore, Linda A.M. Janssen, Siranoush Manoukian, Eva Gross, Kelly J. Sullivan, Doris Steinemann, Susanne Ledig, Alessandra Viel, Christoph Engel, Ana Sánchez de Abajo, Nina Ditsch, Sandra Bonache, Maria A. Caligo, Katharina Pfeifer, Thomas Haaf, Christian Sutter, Eric Hahnen, Laura Matricardi, Marc Tischkowitz, Alex Teulé, Katherine M. Tucker, Jutta Giesecke, Silvia Tognazzo, Gemma Montalban, Carolina Gómez, Anders Kvist, Joanna Lim, Alison H. Trainer, Rachel Susman, Judit Horvath, Amanda B. Spurdle, Mirjam Larsen, Therese Törngren, Mónica Salinas, Nicholas Pachter, Rachel Austin, Nicola K. Poplawski, C Zeder-Göß, Juliane Ramser, Julia Ritter, Anne Sophie Vesper, Paola Concolino, D. Gareth Evans, Clemens R. Müller, Matilde Navarro, Sara Torres-Esquius, Claus R. Bartram, Laura Cortesi, Jacopo Azzollini, Marion Harris, Edward M. Clarke, Marion Kiechle, Lídia Feliubadaló, Almuth Caliebe, Karen N. Herold, Charlotte Kvist Lautrup, Anne S. Quante, Gardenia Vargas-Parra, Michael T. Parsons, Pietro Cavalli, Hongyan Li, Rodrigo Augusto Depieri Michelli, Irene Feroce, Achim Wöckel, Kerstin Wieland, Silke Kaulfuß, Soo Hwang Teo, Angela Velasco, Capucine Delnatte, Marta Pineda, Marion van Mackelenbergh, Eva Montes, Angela Toss, Rita K. Schmutzler, William D. Foulkes, Alvaro N.A. Monteiro, Jan Hauke, Monica Marabelli, Miguel de la Hoya, Sara Gutiérrez-Enríquez, Esther Darder, Simona Agata, Amanda E. Toland, Bernardo Bonanni, Liliana Varesco, Orland Diez, Andreas Rump, Virginie Caux-Moncoutier, Gaetana Gambino, Markus Loeffler, Claude Houdayer, Elena Barbieri, Adrià López-Fernández, et. al., Universidade do Minho, QIMR Berghofer Medical Research Institute, Chinese Academy of Geological Sciences [Beijing] (CAGS), Ministry of Land and Resources (MLR), Department of Gynaecology and Obstetrics, University Hospital of Cologne [Cologne]-Centre of Familial Breast and Ovarian Cancer-Centre for Integrated Oncology (CIO), Programa de Càncer Hereditari, Unitat de Diagnòstic Molecular, Laboratori de Recerca Translacional, Institut Català d'Oncologia-IDIBELL, Department of Clinical Genetics, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA), Helsinki University Central Hospital, University Hospital of Schleswig-Holstein-Christian-Albrechts-Universität zu Kiel (CAU), Università degli Studi di Milano [Milano] (UNIMI), Medical Oncology Department, Vall d'Hebron University Hospital [Barcelona], Institute of Human Genetics, Universität Heidelberg [Heidelberg], Fundación Pública Galega de Medicina Xenómica-SERGAS & Grupo de Medicina Xenómica-USC, CIBER-ER, Division of Cancer Prevention and Genetics, Department of Oncology, Clinical Sciences, Lund University [Lund]-Skåne University Hospital, Genetic Counseling and Hereditary Cancer Programme, Catalan Institute of Oncology, Molecular Oncology Laboratory, Hospital Clínico San Carlos, Institut Curie [Paris], Programa de Consell Genètic en Càncer, Institut Català d'Oncologia, Girona-IdIBGi, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos [Madrid, Spain] (IdISSC), Centre René Gauducheau, CRLCC René Gauducheau, Institut de biochimie et génétique cellulaires (IBGC), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Oncogenetics Laboratory, Vall d'Hebron Institute of Oncology (VHIO), Ludwig-Maximilians-Universität München (LMU), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Genetics, University of Southampton, Departament of Genetics and Pathology, Uppsala University-Rudbeck Laboratory, Department of Genomic Medicine, University of Manchester [Manchester], Department of Medical Genetics, Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU)-Centre of Familial Breast and Ovarian Cancer, Obstetrics and Gynaecology, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Institüt für Humangenetik [Würzburg], Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Institute of Chemistry [Budapest], Faculty of Sciences [Budapest], Eötvös Loránd University (ELTE)-Eötvös Loránd University (ELTE), Service de Biochimie et de Biologie Moléculaire [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), I. Frauenklinik, Klinikum der Ludwig-Maximilians-Universitaet, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Biochemistry, Pharmacology and Genetics, Odense University Hospital, Department of Oncology, Lund University [Lund]-Clinical Sciences, Genetic Medicine, Manchester Academic Health Sciences Centre-Central Manchester University Hospitals, Institute for Medical Informatics, Department of Gynecology and Obstetrics, University Medical Center Schleswig-Holstein, Unit of Medical Genetics, Fondazione IRCCS Istituto Nazionale Tumouri (INT), Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV - IRCCS, University Medical Center Kiel, Department of Obstetrics and Gynecology, University Hospital Düsseldorf-Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Medical Genetics Unit, Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Department of Biochemistry, Section of Molecular Diagnostics, Laboratoire d'Oncologie Moléculaire Humaine, Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université Lille Nord de France (COMUE)-UNICANCER-Université Lille Nord de France (COMUE)-UNICANCER, Institute of Cell and Molecular Pathology, Medizinische Hochschule Hannover (MHH), University of California [Santa Cruz] (UCSC), University of California, Heidelberg University Hospital [Heidelberg], International Agency for Cancer Research (IACR), Programa de Consejo Genético en Cáncer, Instituto Catalán de Oncología-IDIBELL, L'Hospitalet, Programa de Diagnòstic Molecular de Càncer Hereditari, Laboratori de Recerca Translacional, Institut Català d'Oncologia-IDIBELL, Hospital Duran i Reynals, Hospitalet de Llobregat, Unit of Hereditary Cancers, Istituto Nazionale per la Ricerca sul Cancro, CIBER de Enfermedades Raras (CIBERER), Unit of Experimental Oncology 1, Centro di Riferimento Oncologico, University of Otago [Dunedin, Nouvelle-Zélande], Institute of Pathology, Department of Gynecology, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), King‘s College London, Molecular Diagnostic Unit, IDIBELL-Catalan Institute of Oncology, Unit of Molecular Bases of Genetic Risk and Genetic Testing, Fondazione IRCCS Istituto Nazionale Tumouri (INT)-Fondazione Istituto FIRC di Oncologia Molecolare, Institute for Medical Informatics, Statistics and Epidemiology [Leipzig] (IMISE), Universität Leipzig [Leipzig], Division of Molecular Gynaeco-Oncology, Department of Gynaecology and Obstetrics, Clinical Center University of Cologne, Medicum, Research Programs Unit, Genome-Scale Biology (GSB) Research Program, Kristiina Aittomäki / Principal Investigator, HUSLAB, Department of Medical and Clinical Genetics, HUS Gynecology and Obstetrics, University Management, University of Helsinki, Università degli Studi di Milano = University of Milan (UNIMI), Universität Heidelberg [Heidelberg] = Heidelberg University, Department of Genetics and Pathology, Uppsala University, Julius-Maximilians-Universität Würzburg (JMU)-Centre of Familial Breast and Ovarian Cancer, Julius-Maximilians-Universität Würzburg (JMU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università degli Studi di Firenze = University of Florence (UniFI), Université de Lille-UNICANCER-Université de Lille-UNICANCER, University of California [Santa Cruz] (UC Santa Cruz), University of California (UC), Universität Leipzig, University of Cologne, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Polikliniek (9), and Klinische Genetica

Subjects
Male, Multifactorial Inheritance, BRCA1, BRCA2, classification, clinical, multifactorial, quantitative, uncertain significance, variant, Alternative Splicing, BRCA1 Protein, BRCA2 Protein, Computational Biology, Early Detection of Cancer, Female, Genetic Predisposition to Disease, Humans, Likelihood Functions, Neoplasms, Mutation, Missense, Medicina Básica [Ciências Médicas], Settore MED/03 - GENETICA MEDICA, GUIDELINES, Genetic analysis, CLINGEN, SEQUENCE VARIANTS, Missense mutation, FUNCTIONAL ASSAYS, Genetics (clinical), BRCA1, BRCA2, quantitative, clinical, classification, multifactorial, variant, uncertain significance, 0303 health sciences, education.field_of_study, 030305 genetics & heredity, 1184 Genetics, developmental biology, physiology, SPLICING ANALYSIS, OVARIAN, BRCA2 Protein/genetics, 3. Good health, ddc, Mutation (genetic algorithm), Ciências Médicas::Medicina Básica, Medical genetics, Special Articles, medicine.medical_specialty, Posterior probability, Population, Computational biology, Biology, INTEGRATED EVALUATION, 03 medical and health sciences, Special Article, medicine, Genetics, BREAST-CANCER, Genetic variability, ddc:610, education, 030304 developmental biology, Tumors, Science & Technology, Proteins, Computational Biology/methods, RISKS, Mutation, BRCA1 Protein/genetics, 3111 Biomedicine, Missense, Proteïnes, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Genètica, Neoplasms/diagnosis
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., Ohio State University Comprehensive Cancer Center Barretos Cancer Hospital. Grant Number: FINEP ‐ CT‐INFRA (02/2010) Breast Cancer Foundation of New Zealand Canadian Institutes of Health Research. Grant Number: PSR‐SIIRI‐701 Cancer Research UK. Grant Numbers: C8197/A16565, C5047/A8384, C1281/A12014, C12292/A11174, C1287/A10710, C1287/A10118, C1287/A16563, C5047/A10692, C5047/A15007 Department of Defence, USA. Grant Number: W81XWH‐10‐1‐0341 Helsinki University Hospital Research fund Scientific Foundation Asociación Española Contra el Cáncer Leiden University Medical Centre. Grant Number: Grant 30.925 Generalitat de Catalunya. Grant Numbers: PERIS_MedPerCan, URDCat, 2017SGR1282, 2017SGR496 Royal Society of New Zealand Cancer Council Victoria Netherlands Organization for Scientific Research (NWO). Grant Number: Grant 017.008.022 Breast Cancer Research Foundation Cancer Foundation of Western Australia EU H2020. Grant Number: 634935 Fundación Mutua Madrileña Seventh Framework Programme. Grant Numbers: 634935, 223175, 633784 Cancer Council South Australia Government of Galicia. Grant Number: Consolidation and structuring program: IN607B Cancer Council Tasmania Italian Association of Cancer Research. Grant Number: 15547 Queensland Cancer Fund AstraZeneca National Institute of Health (USA). Grant Numbers: 1U19 CA148065‐01, CA128978, CA192393, 1U19 CA148537, P50 CA1162091, CA116167, 1U19 CA148112 Newcastle University Dutch Cancer Society KWF. Grant Numbers: KWF/Pink Ribbon‐11704, UL2012‐5649 National Institute for Health Research. Grant Number: Manchester Biomedical Research centre (IS‐BRC‐1215 National Council of Technological and Scientific Development (CNPq) Instituto de Salud Carlos III. Grant Numbers: FIS PI15/00355, FIS PI13/01711, CIBERONC, FIS PI16/01218, PI16/00563 French National Institute of Cancer National Breast Cancer Foundation National Health and Medical Research Council. Grant Numbers: ID1061778, ID1104808 Carlos III National Health Centro de Investigación Biomédica en Red de Enferemdades Raras. Grant Number: ACCI 2016: ER17P1AC7112/2018 Cancer Council NSW Deutsche Krebshilfe. Grant Numbers: (#110837, #70111850 Fondazione Pisa. Grant Number: Grant “Clinical characterization of BRCA 1/2 Mis

Published
2019

17. Towards controlled terminology for reporting germline cancer susceptibility variants: an ENIGMA report

Author

Arjen R. Mensenkamp, Paolo Radice, Mark E. Robson, Emma Tudini, Amanda B. Spurdle, Susan M. Domchek, Melissa A. Brown, Logan C. Walker, Miguel de la Hoya, Sean V. Tavtigian, Diana Eccles, Leslie Burke, Thilo Dörk, Clare Turnbull, Antonis C. Antoniou, Michael T. Parsons, Stephanie Greville-Heygate, Maaike P.G. Vreeswijk, Marc Tischkowitz, Alvaro N.A. Monteiro, Helen V. Firth, Spurdle, Amanda B [0000-0003-1337-7897], de la Hoya, Miguel [0000-0002-8113-1410], Parsons, Michael T [0000-0003-3242-8477], Radice, Paolo [0000-0001-6298-4111], Eccles, Diana M [0000-0002-9935-3169], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, genetic variant, Vocabulary, media_common.quotation_subject, Genes, BRCA2, Genes, BRCA1, Computational biology, Biology, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, All institutes and research themes of the Radboud University Medical Center, International Classification of Diseases, Terminology as Topic, Genetic variation, Controlled vocabulary, Genetics, medicine, Biomarkers, Tumor, Humans, Genetic Predisposition to Disease, Genetics (clinical), interpretation, Germ-Line Mutation, Genetic testing, media_common, vocabulary, reporting, Massive parallel sequencing, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], medicine.diagnostic_test, Gene Expression Profiling, Cancer, Computational Biology, Genetic Variation, High-Throughput Nucleotide Sequencing, Neoplasms, Germ Cell and Embryonal, medicine.disease, cancer susceptibility, Genetic architecture, 3. Good health, 030104 developmental biology, Vocabulary, Controlled, 030220 oncology & carcinogenesis, Mendelian inheritance, symbols
Abstract

The vocabulary currently used to describe genetic variants and their consequences reflects many years of studying and discovering monogenic disease with high penetrance. With the recent rapid expansion of genetic testing brought about by wide availability of high-throughput massively parallel sequencing platforms, accurate variant interpretation has become a major issue. The vocabulary used to describe single genetic variants in silico, in vitro, in vivo and as a contributor to human disease uses terms in common, but the meaning is not necessarily shared across all these contexts. In the setting of cancer genetic tests, the added dimension of using data from genetic sequencing of tumour DNA to direct treatment is an additional source of confusion to those who are not experienced in cancer genetics. The language used to describe variants identified in cancer susceptibility genetic testing typically still reflects an outdated paradigm of Mendelian inheritance with dichotomous outcomes. Cancer is a common disease with complex genetic architecture; an improved lexicon is required to better communicate among scientists, clinicians and patients, the risks and implications of genetic variants detected. This review arises from a recognition of, and discussion about, inconsistencies in vocabulary usage by members of the ENIGMA international multidisciplinary consortium focused on variant classification in breast-ovarian cancer susceptibility genes. It sets out the vocabulary commonly used in genetic variant interpretation and reporting, and suggests a framework for a common vocabulary that may facilitate understanding and clarity in clinical reporting of germline genetic tests for cancer susceptibility.

Published
2019

18. BRCA1 and BRCA2 5′ noncoding region variants identified in breast cancer patients alter promoter activity and protein binding

Author

Eliseos J. Mucaki, Stacey L. Edwards, Marinus J. Blok, Jana Soukupova, Mariana Borecka, Marta Santamariña, Marketa Janatova, Paolo Peterlongo, Ana Vega, Ben C. Shirley, Amanda B. Spurdle, Peter K. Rogan, Gaetana Gambino, Phillip J. Whiley, Lenka Stolarova, Petra Zemankova, O. Diez, Siranoush Manoukian, Thomas van Overeem Hansen, David E. Goldgar, Bernardo Bonanni, Emma Tudini, Sara Gutiérrez-Enríquez, Leslie Burke, Elizabeth Santana dos Santos, Michael T. Parsons, Kathleen Claes, Jan Sevcik, Kim De Leeneer, Melissa A. Brown, Paolo Radice, Maria Caligo, Etienne Rouleau, Sandrine M. Caputo, Alejandro Moles-Fernández, Maria Rossing, Klara Lhotova, RS: GROW - R4 - Reproductive and Perinatal Medicine, and MUMC+: DA KG Lab Centraal Lab (9)

Subjects
0301 basic medicine, SUSCEPTIBILITY, Genome, Biochemistry, 0302 clinical medicine, Medicine and Health Sciences, TRANSCRIPTION, Age of Onset, Promoter Regions, Genetic, Research Articles, Genetics (clinical), GENE-EXPRESSION, Genetics, RISK, Tumor, BRCA1 Protein, BRCA1, BRCA2, breast cancer, promoter, transcription, variants of unknown clinical significance (VUS), 5' Untranslated Regions, BRCA2 Protein, Breast Neoplasms, CCAAT-Binding Factor, Cell Line, Tumor, Female, Genetic Predisposition to Disease, Humans, MCF-7 Cells, PAX5 Transcription Factor, Protein Binding, Germ-Line Mutation, ASSOCIATION, 3. Good health, 030220 oncology & carcinogenesis, Research Article, GERMLINE VARIANTS, REGULATORY ELEMENTS, Biology, DNA sequencing, OVARIAN-CANCER, Cell Line, Promoter Regions, 03 medical and health sciences, Breast cancer, Genetic, medicine, Clinical significance, Allele frequency, COMPLEX, MUTATIONS, Biology and Life Sciences, Promoter, medicine.disease, Minor allele frequency, 030104 developmental biology
Abstract

© 2018 The Authors. Human Mutation published by Wiley Periodicals, Inc. The widespread use of next generation sequencing for clinical testing is detecting an escalating number of variants in noncoding regions of the genome. The clinical significance of the majority of these variants is currently unknown, which presents a significant clinical challenge. We have screened over 6,000 early-onset and/or familial breast cancer (BC) cases collected by the ENIGMA consortium for sequence variants in the 5′ noncoding regions of BC susceptibility genes BRCA1 and BRCA2, and identified 141 rare variants with global minor allele frequency < 0.01, 76 of which have not been reported previously. Bioinformatic analysis identified a set of 21 variants most likely to impact transcriptional regulation, and luciferase reporter assays detected altered promoter activity for four of these variants. Electrophoretic mobility shift assays demonstrated that three of these altered the binding of proteins to the respective BRCA1 or BRCA2 promoter regions, including NFYA binding to BRCA1:c.-287C>T and PAX5 binding to BRCA2:c.-296C>T. Clinical classification of variants affecting promoter activity, using existing prediction models, found no evidence to suggest that these variants confer a high risk of disease. Further studies are required to determine if such variation may be associated with a moderate or low risk of BC.

Published
2018

19. Substantial evidence for the clinical significance of missense variant BRCA1 c.5309G > T p.(Gly1770Val)

Author

Emma Tudini, Setareh Moghadasi, Conxi Lázaro, Dieter Niederacher, Lizet E. van der Kolk, Ans M.W. van den Ouweland, Lídia Feliubadaló, Barbara Wappenschmidt, Michael T. Parsons, Amanda B. Spurdle, and Clinical Genetics

Subjects
0301 basic medicine, Cancer Research, DNA Repair, DNA repair, Posterior probability, Mutation, Missense, Breast Neoplasms, Biology, Conserved sequence, Evolution, Molecular, Mice, 03 medical and health sciences, Bayes' theorem, Animals, Humans, Missense mutation, Genetic Predisposition to Disease, Clinical significance, Breast and ovarian cancer, Conserved Sequence, Sequence (medicine), Genetics, Evolutionary conservation, Multiple sequence alignment, BRCA1 Protein, Bayes Theorem, BRCA1, Multifactorial likelihood analysis, 030104 developmental biology, Oncology, Variant classification, Female, Sequence Alignment
Abstract

Classification of rare BRCA1 missense variants presents a major challenge for the counseling and treatment of patients. Variant classification can be complicated by conflicting lines of evidence. BRCA1 c.5309G>T p.(Gly1770Val) has been shown to abrogate BRCA1 protein homologous DNA repair; however, multiple sequence alignment demonstrates a lack of sequence conservation at this position, suggesting that glycine at position 1770 may not be essential for cellular maintenance in humans. We analyzed clinical information to resolve the classification of BRCA1 c.5309G>T p.(Gly1770Val). We performed multifactorial likelihood analysis combining segregation data for 14 informative families, and breast tumor histopathological data for 17 variant carriers, ascertained through the ENIGMA consortium. Bayes segregation analysis gave a likelihood ratio of 101:1 in favor of pathogenicity. The vast majority of breast tumors showed features indicative of pathogenic variant carrier status, resulting in a likelihood ratio of 15800794:1 towards pathogenicity. Despite a low prior probability of pathogenicity (0.03) based on bioinformatic prediction, multifactorial likelihood analysis including segregation and histopathology analysis gave a posterior probability of > 0.99 and final classification of Pathogenic. We provide evidence that BRCA1 c.5309G>T p.(Gly1770Val), previously described as a Moroccan founder variant, should be treated as a disease-causing variant despite a lack of evolutionary conservation at this amino acid position. Additionally, we stress that bioinformatic information should be used in combination with other data, either direct clinical evidence or some form of clinical calibration, to arrive at a final clinical classification.

Published
2018

20. The BRCA2 c.68-7T A variant is not pathogenic: A model for clinical calibration of spliceogenicity

Author

Mara, Colombo, Irene, Lòpez-Perolio, Huong D, Meeks, Laura, Caleca, Michael T, Parsons, Hongyan, Li, Giovanna, De Vecchi, Emma, Tudini, Claudia, Foglia, Patrizia, Mondini, Siranoush, Manoukian, Raquel, Behar, Encarna B Gómez, Garcia, Alfons, Meindl, Marco, Montagna, Dieter, Niederacher, Ane Y, Schmidt, Liliana, Varesco, Barbara, Wappenschmidt, Manjeet K, Bolla, Joe, Dennis, Kyriaki, Michailidou, Qin, Wang, Kristiina, Aittomäki, Irene L, Andrulis, Hoda, Anton-Culver, Volker, Arndt, Matthias W, Beckmann, Alicia, Beeghly-Fadel, Javier, Benitez, Bram, Boeckx, Natalia V, Bogdanova, Stig E, Bojesen, Bernardo, Bonanni, Hiltrud, Brauch, Hermann, Brenner, Barbara, Burwinkel, Jenny, Chang-Claude, Don M, Conroy, Fergus J, Couch, Angela, Cox, Simon S, Cross, Kamila, Czene, Peter, Devilee, Thilo, Dörk, Mikael, Eriksson, Peter A, Fasching, Jonine, Figueroa, Olivia, Fletcher, Henrik, Flyger, Marike, Gabrielson, Montserrat, García-Closas, Graham G, Giles, Anna, González-Neira, Pascal, Guénel, Christopher A, Haiman, Per, Hall, Ute, Hamann, Mikael, Hartman, Jan, Hauke, Antoinette, Hollestelle, John L, Hopper, Anna, Jakubowska, Audrey, Jung, Veli-Matti, Kosma, Diether, Lambrechts, Loid, Le Marchand, Annika, Lindblom, Jan, Lubinski, Arto, Mannermaa, Sara, Margolin, Hui, Miao, Roger L, Milne, Susan L, Neuhausen, Heli, Nevanlinna, Janet E, Olson, Paolo, Peterlongo, Julian, Peto, Katri, Pylkäs, Elinor J, Sawyer, Marjanka K, Schmidt, Rita K, Schmutzler, Andreas, Schneeweiss, Minouk J, Schoemaker, Mee Hoong, See, Melissa C, Southey, Anthony, Swerdlow, Soo H, Teo, Amanda E, Toland, Ian, Tomlinson, Thérèse, Truong, Christi J, van Asperen, Ans M W, van den Ouweland, Lizet E, van der Kolk, Robert, Winqvist, Drakoulis, Yannoukakos, Wei, Zheng, Alison M, Dunning, Douglas F, Easton, Alex, Henderson, Frans B L, Hogervorst, Louise, Izatt, Kenneth, Offitt, Lucy E, Side, Elizabeth J, van Rensburg, Study, Embrace, Study, Hebon, Lesley, McGuffog, Antonis C, Antoniou, Georgia, Chenevix-Trench, Amanda B, Spurdle, David E, Goldgar, Miguel de la, Hoya, and Paolo, Radice

Subjects
BRCA2 Protein, Base Sequence, Models, Genetic, digital PCR, multifactorial likelihood analysis, Mitomycin, RNA Splicing, spliceogenic variants, Genetic Variation, Exons, BRCA2, Cell Line, Calibration, Humans, Female, Genetic Predisposition to Disease, RNA, Messenger, Research Articles, quantitative real‐time PCR, Research Article
Abstract

Although the spliceogenic nature of the BRCA2 c.68‐7T > A variant has been demonstrated, its association with cancer risk remains controversial. In this study, we accurately quantified by real‐time PCR and digital PCR (dPCR), the BRCA2 isoforms retaining or missing exon 3. In addition, the combined odds ratio for causality of the variant was estimated using genetic and clinical data, and its associated cancer risk was estimated by case‐control analysis in 83,636 individuals. Co‐occurrence in trans with pathogenic BRCA2 variants was assessed in 5,382 families. Exon 3 exclusion rate was 4.5‐fold higher in variant carriers (13%) than controls (3%), indicating an exclusion rate for the c.68‐7T > A allele of approximately 20%. The posterior probability of pathogenicity was 7.44 × 10−115. There was neither evidence for increased risk of breast cancer (OR 1.03; 95% CI 0.86–1.24) nor for a deleterious effect of the variant when co‐occurring with pathogenic variants. Our data provide for the first time robust evidence of the nonpathogenicity of the BRCA2 c.68‐7T > A. Genetic and quantitative transcript analyses together inform the threshold for the ratio between functional and altered BRCA2 isoforms compatible with normal cell function. These findings might be exploited to assess the relevance for cancer risk of other BRCA2 spliceogenic variants.

Published
2017

21. Abstract 1859: Bioinformatic and experimental evaluation of regulatory variants in breast cancer susceptibility genes

Author

Amanda B. Spurdle, Paolo Peterlongo, Ana Vega, Thomas van Overeem Hansen, Siranoush Manoukian, Maria A. Caligo, Melissa A. Brown, Philip J. Whiley, Brooke L. Brewster, Paolo Radice, Leslie Burke, Emma Tudini, Jan Sevcik, Marta Santamariña Pena, Etienne Rouleau, and Gaetana Gambino

Subjects
Genetics, Untranslated region, Cancer Research, Cancer, Biology, medicine.disease, Genome, Germline, Breast cancer, Oncology, Regulatory sequence, medicine, Allele, Gene
Abstract

Many germline DNA sequence variants in gene regulatory elements are associated with an increased risk of cancer. These include large genomic deletions of the promoter of the BRCA1 gene, through to single nucleotide variants in the promoter, UTRs and long-range enhancers of multiple other cancer related genes. Next generation sequence analysis of early onset and familial breast cancer cases is currently identifying an escalating number of variants in non-coding regions of the genome, however for most of these the significance in unknown. This project aims to determine the functional and clinical significance of breast cancer associated variants in regulatory regions of BRCA1 and BRCA2, as part of an international collaborative project arising from the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium. To date over two hundred variants mapping to promoter, UTR and deep intronic regions have been identified in early onset or familial breast cancer patients that have no identifiable coding or splicing changes in BRCA1 or BRCA2. Through a pipeline of bioinformatics analyses using ENCODE datasets, these variants have been prioritized for experimental evaluation. This has lead to the identification of several variants that significantly alter the regulation of BRCA1 or BRCA2 expression, through mechanisms including altered binding of transcription factors and microRNAs. These studies will lay the groundwork for comprehensive statistical analyses, in which bioinformatics and experimental data is combined with clinical and genetic data to establish multifactorial risk prediction models that can ultimately be used in a clinical setting. Citation Format: Jan Sevcik, Leslie Burke, Gaetana Gambino, Brooke L. Brewster, Emma Tudini, Philip J. Whiley, Siranoush Manoukian, ENIGMA Consortium, Thomas van Overeem Hansen, Marta Santamariña Pena, Ana Vega, Maria A. Caligo, Paolo Radice, Paolo Peterlongo, Etienne Rouleau, Amanda B. Spurdle, Melissa A. Brown. Bioinformatic and experimental evaluation of regulatory variants in breast cancer susceptibility genes. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1859.

Published
2016

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