The known unknown: the challenges of genetic variants of uncertain significance in clinical practice.
TLDR
The issues raised by VUSs in clinical practice are focused on, and paths forward are suggested to suggest paths forward.Abstract:
As genetic testing technology has advanced, allowing scientists to obtain much of the raw data from our DNA, their ability to interpret these data has struggled to keep up. The result is the ubiquity of variants of uncertain significance (VUSs): findings from genetic testing for which the clinical significance is currently unresolved. What to do when these results are found is a problem that has vexed laboratories, clinicians, and patients alike. In this paper, I focus on the issues raised by VUSs in clinical practice, and suggest paths forward.read more
Citations
More filters
Journal ArticleDOI
Is it time to change the reference genome
TL;DR: It is suggested that switching to a consensus reference would offer important advantages over the continued use of the current reference with few disadvantages, and its use for variant-calling is focused on.
Journal ArticleDOI
Genetics of dilated cardiomyopathy: practical implications for heart failure management
TL;DR: A broad perspective on the genetic causes of dilated cardiomyopathy is given to provide a context for a discussion of the pragmatic use of genetic testing in heart failure clinics for patients presenting with new-onset dilated heart failure.
Journal ArticleDOI
Drug Repurposing for Rare Diseases.
Helen I. Roessler,Nine V A M Knoers,Nine V A M Knoers,Mieke M. van Haelst,Mieke M. van Haelst,Gijs van Haaften +5 more
TL;DR: A review of applied methodologies, recent accomplished progress, and challenges associated in drug repurposing for rare diseases can be found in this paper, where the authors review applied methods, recent accomplishments, and the challenges associated with drug re-use for rare disease.
Journal ArticleDOI
Diagnostic yield and clinical utility of whole exome sequencing using an automated variant prioritization system, EVIDENCE.
Go Hun Seo,Taeho Kim,In Hee Choi,Jung Young Park,Jungsul Lee,Sehwan Kim,Dhong gun Won,Arum Oh,Yena Lee,Jeongmin Choi,Hajeong Lee,Hee Gyung Kang,Hee Yeon Cho,Min Hyun Cho,Yoon Jeon Kim,Young Hee Yoon,Baik Lin Eun,Robert J. Desnick,Changwon Keum,Beom Hee Lee +19 more
TL;DR: This new, automated variant interpretation system facilitated the diagnosis of various genetic diseases with a 42.7% diagnostic yield in patients with suspected genetic disorders.
Journal ArticleDOI
Evaluation of Germline Genetic Testing Criteria in a Hospital-Based Series of Women With Breast Cancer
Siddhartha Yadav,Chunling Hu,Steven N. Hart,Nicholas J. Boddicker,Eric C. Polley,Jie Na,Rohan Gnanaolivu,Kun Y. Lee,Tricia Lindstrom,Sebastian M. Armasu,Patrick D. Fitz-Gibbon,Karthik Ghosh,Daniela L. Stan,Sandhya Pruthi,Lonzetta Neal,Nicole P. Sandhu,Deborah J. Rhodes,Christine L. Klassen,Prema P. Peethambaram,Tufia C. Haddad,Janet E. Olson,Tanya L. Hoskin,Matthew P. Goetz,Susan M. Domchek,Judy C. Boughey,Kathryn J. Ruddy,Fergus J. Couch +26 more
TL;DR: A substantial proportion of women with breast cancer carrying germline pathogenic variants in predisposition genes do not qualify for testing by the National Comprehensive Cancer Network criteria, and expansion of NCCN criteria to include all women diagnosed at ≤ 65 years of age improves the sensitivity of the selection criteria without requiring testing of all women.
References
More filters
Journal ArticleDOI
An Abundance of Rare Functional Variants in 202 Drug Target Genes Sequenced in 14,002 People
Matthew R. Nelson,Daniel Wegmann,Margaret G. Ehm,Darren Kessner,Pamela L. St. Jean,Claudio J. Verzilli,Judong Shen,Zheng-Zheng Tang,Silviu Alin Bacanu,Dana Fraser,Liling Warren,Jennifer L. Aponte,Matthew Zawistowski,Xiao Liu,Hao Zhang,Yong Zhang,Jun Li,Yun Li,Li Li,Peter Woollard,Simon Topp,Matthew D. Hall,Keith Nangle,Jun Wang,Gonçalo R. Abecasis,Lon R. Cardon,Sebastian Zöllner,John C. Whittaker,Stephanie L. Chissoe,John Novembre,Vincent Mooser +30 more
TL;DR: It is concluded that because of rapid population growth and weak purifying selection, human populations harbor an abundance of rare variants, many of which are deleterious and have relevance to understanding disease risk.
Journal ArticleDOI
Genetic Misdiagnoses and the Potential for Health Disparities
Arjun K. Manrai,Birgit Funke,Heidi L. Rehm,Morten S. Olesen,Bradley A. Maron,Peter Szolovits,David M. Margulies,Joseph Loscalzo,Isaac S. Kohane +8 more
TL;DR: The misclassification of benign variants as pathogenic variants that were found in this study shows the need for sequencing the genomes of diverse populations, both in asymptomatic controls and the tested patient population.
Journal ArticleDOI
Gaps in Incorporating Germline Genetic Testing Into Treatment Decision-Making for Early-Stage Breast Cancer.
Allison W. Kurian,Yun Li,Ann S. Hamilton,Kevin C. Ward,Sarah T. Hawley,Monica Morrow,M. Chandler McLeod,Reshma Jagsi,Steven J. Katz +8 more
TL;DR: Many patients with breast cancer are tested without ever seeing a genetic counselor, suggesting a limited understanding of results that some surgeons share, and the need to address challenges in personalized communication about genetic testing.
Journal ArticleDOI
Genetic purgatory and the cardiac channelopathies: Exposing the variants of uncertain/unknown significance issue
TL;DR: The purpose of this review article is to fully expose the VUS issue as it relates to the cardiac channelopathies and make the cardiologists/geneticsists/genetic counselors who order such genetic tests believers in genetic purgatory.
Journal ArticleDOI
The counsellees' view of an unclassified variant in BRCA1/2: recall, interpretation, and impact on life.
TL;DR: Unclassified variants (UVs, variants of uncertain clinical significance) are found in 13% of all BRCA1/2 mutation analyses, and little is known about the counsellees' recall and interpretation of a UV, and its psychosocial/medical impact.
Related Papers (5)
Analysis of protein-coding genetic variation in 60,706 humans
Monkol Lek,Konrad J. Karczewski,Konrad J. Karczewski,Eric Vallabh Minikel,Eric Vallabh Minikel,Kaitlin E. Samocha,Eric Banks,Timothy Fennell,Anne H. O’Donnell-Luria,Anne H. O’Donnell-Luria,Anne H. O’Donnell-Luria,James S. Ware,Andrew J. Hill,Andrew J. Hill,Andrew J. Hill,Beryl B. Cummings,Beryl B. Cummings,Taru Tukiainen,Taru Tukiainen,Daniel P. Birnbaum,Jack A. Kosmicki,Laramie E. Duncan,Laramie E. Duncan,Karol Estrada,Karol Estrada,Fengmei Zhao,Fengmei Zhao,James Zou,Emma Pierce-Hoffman,Emma Pierce-Hoffman,Joanne Berghout,David Neil Cooper,Nicole A. Deflaux,Mark A. DePristo,Ron Do,Jason Flannick,Jason Flannick,Menachem Fromer,Laura D. Gauthier,Jackie Goldstein,Jackie Goldstein,Namrata Gupta,Daniel P. Howrigan,Daniel P. Howrigan,Adam Kiezun,Mitja I. Kurki,Mitja I. Kurki,Ami Levy Moonshine,Pradeep Natarajan,Lorena Orozco,Gina M. Peloso,Gina M. Peloso,Ryan Poplin,Manuel A. Rivas,Valentin Ruano-Rubio,Samuel A. Rose,Douglas M. Ruderfer,Khalid Shakir,Peter D. Stenson,Christine Stevens,Brett Thomas,Brett Thomas,Grace Tiao,María Teresa Tusié-Luna,Ben Weisburd,Hong-Hee Won,Dongmei Yu,David Altshuler,David Altshuler,Diego Ardissino,Michael Boehnke,John Danesh,Stacey Donnelly,Roberto Elosua,Jose C. Florez,Jose C. Florez,Stacey Gabriel,Gad Getz,Gad Getz,Stephen J. Glatt,Christina M. Hultman,Sekar Kathiresan,Markku Laakso,Steven A. McCarroll,Steven A. McCarroll,Mark I. McCarthy,Mark I. McCarthy,Dermot P.B. McGovern,Ruth McPherson,Benjamin M. Neale,Benjamin M. Neale,Aarno Palotie,Shaun Purcell,Danish Saleheen,Jeremiah M. Scharf,Pamela Sklar,Patrick F. Sullivan,Patrick F. Sullivan,Jaakko Tuomilehto,Ming T. Tsuang,Hugh Watkins,Hugh Watkins,James G. Wilson,Mark J. Daly,Mark J. Daly,Daniel G. MacArthur,Daniel G. MacArthur +106 more
ClinVar: improving access to variant interpretations and supporting evidence.
Melissa J. Landrum,Jennifer M. Lee,Mark L. Benson,Garth Brown,Chen Chao,Shanmuga Chitipiralla,Baoshan Gu,Jennifer Hart,Douglas W. Hoffman,Wonhee Jang,Karen Karapetyan,Kenneth S. Katz,Chunlei Liu,Zenith Maddipatla,Malheiro Aj,Kurt McDaniel,Michael Ovetsky,George R. Riley,George Zhou,J. Bradley Holmes,Brandi L. Kattman,Donna Maglott +21 more