Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results
Sharon E. Plon,Diana Eccles,Douglas F. Easton,William D. Foulkes,Maurizio Genuardi,Marc S. Greenblatt,Frans B. L. Hogervorst,Nicoline Hoogerbrugge,Amanda B. Spurdle,Sean V. Tavtigian +9 more
TLDR
The current state of sequence‐based genetic testing is reviewed, other standardized reporting systems used in oncology are described, and a standardized classification system for application to sequence-based results for cancer predisposition genes is proposed.Abstract:
Genetic testing of cancer susceptibility genes is now widely applied in clinical practice to predict risk of developing cancer. In general, sequence-based testing of germline DNA is used to determine whether an individual carries a change that is clearly likely to disrupt normal gene function. Genetic testing may detect changes that are clearly pathogenic, clearly neutral, or variants of unclear clinical significance. Such variants present a considerable challenge to the diagnostic laboratory and the receiving clinician in terms of interpretation and clear presentation of the implications of the result to the patient. There does not appear to be a consistent approach to interpreting and reporting the clinical significance of variants either among genes or among laboratories. The potential for confusion among clinicians and patients is considerable and misinterpretation may lead to inappropriate clinical consequences. In this article we review the current state of sequence-based genetic testing, describe other standardized reporting systems used in oncology, and propose a standardized classification system for application to sequence-based results for cancer predisposition genes. We suggest a system of five classes of variants based on the degree of likelihood of pathogenicity. Each class is associated with specific recommendations for clinical management of at-risk relatives that will depend on the syndrome. We propose that panels of experts on each cancer predisposition syndrome facilitate the classification scheme and designate appropriate surveillance and cancer management guidelines. The international adoption of a standardized reporting system should improve the clinical utility of sequence-based genetic tests to predict cancer risk.read more
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Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
Sue Richards,Nazneen Aziz,Nazneen Aziz,Sherri J. Bale,David P. Bick,Soma Das,Julie M. Gastier-Foster,Wayne W. Grody,Madhuri Hegde,Elaine Lyon,Elaine B. Spector,Karl V. Voelkerding,Heidi L. Rehm +12 more
TL;DR: Because of the increased complexity of analysis and interpretation of clinical genetic testing described in this report, the ACMG strongly recommends thatclinical molecular genetic testing should be performed in a Clinical Laboratory Improvement Amendments–approved laboratory, with results interpreted by a board-certified clinical molecular geneticist or molecular genetic pathologist or the equivalent.
Journal ArticleDOI
Pheochromocytoma and paraganglioma: An endocrine society clinical practice guideline
Jacques W.M. Lenders,Quan-Yang Duh,Graeme Eisenhofer,Anne Paule Gimenez-Roqueplo,Stefan K.G. Grebe,Mohammad Hassan Murad,Mitsuhide Naruse,Karel Pacak,William F. Young +8 more
TL;DR: This evidence-based guideline recommends minimally invasive adrenalectomy for most pheochromocytomas with open resection for most paragangliomas and suggests personalized management with evaluation and treatment by multidisciplinary teams with appropriate expertise to ensure favorable outcomes.
Journal ArticleDOI
Gene-Panel Sequencing and the Prediction of Breast-Cancer Risk
Douglas F. Easton,Paul D.P. Pharoah,Antonis C. Antoniou,Marc Tischkowitz,Sean V. Tavtigian,Katherine L. Nathanson,Peter Devilee,Alfons Meindl,Fergus J. Couch,Melissa C. Southey,David E. Goldgar,D. Gareth Evans,Georgia Chenevix-Trench,Nurul Hidayah Ab Rahman,Mark E. Robson,Susan M. Domchek,William D. Foulkes +16 more
TL;DR: An international group of cancer geneticists review the level of evidence for the association of gene variants with the risk of breast cancer and it is difficult to draw firm conclusions from the data because of ascertainment bias and the lack of data from large populations.
Journal ArticleDOI
Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease
David Neil Cooper,Michael Krawczak,Constantin Polychronakos,Chris Tyler-Smith,Hildegard Kehrer-Sawatzki +4 more
TL;DR: The evidence for reduced penetrance being a widespread phenomenon in human genetics is summarized and some of the molecular mechanisms that may help to explain this enigmatic characteristic of human inherited disease are explored.
Journal ArticleDOI
Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene
Patrick R. Sosnay,Karen R. Siklosi,Fredrick Van Goor,Kyle Kaniecki,Kyle Kaniecki,Haihui Yu,Neeraj Sharma,Anabela S. Ramalho,Anabela S. Ramalho,Margarida D. Amaral,Margarida D. Amaral,Ruslan Dorfman,Julian Zielenski,David L. Masica,Rachel Karchin,Linda Millen,Philip Thomas,George P. Patrinos,Mary Corey,Michelle Huckaby Lewis,Johanna M. Rommens,Carlo Castellani,Christopher M. Penland,Garry R. Cutting +23 more
TL;DR: It is illustrated that sourcing data directly from well-phenotyped subjects can address the gap in the ability to interpret clinically relevant genomic variation in patients with cystic fibrosis.
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A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer
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TL;DR: Four SNPs in intron 2 of FGFR2 (which encodes a receptor tyrosine kinase and is amplified or overexpressed in some breast cancers) that were highly associated with breast cancer were identified and confirmed in 1,776 affected individuals and 2,072 controls from three additional studies.
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Clinical Characteristics of Individuals With Germline Mutations in BRCA1 and BRCA2: Analysis of 10,000 Individuals
Thomas S. Frank,Amie M. Deffenbaugh,Julia Reid,Mark Hulick,Brian E. Ward,Beth Lingenfelter,Kathi L. Gumpper,Thomas Scholl,Sean V. Tavtigian,Dmitry Pruss,Gregory C. Critchfield +10 more
TL;DR: Specific features of personal and family history can be used to assess the likelihood of identifying a mutation in BRCA1 or BRCa2 in individuals tested in a clinical setting.
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ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007
C. Sue Richards,Sherri J. Bale,Daniel B. Bellissimo,Soma Das,Wayne W. Grody,Madhuri Hegde,Elaine Lyon,Brian E Ward +7 more
TL;DR: The ACMG strongly recommends that the clinical and technical validation of sequence variation detection be performed in a CLIA-approved laboratory and interpreted by a board-certified clinical molecular geneticist or equivalent.
Recommendations for the Care of Individuals With an Inherited Predisposition to Lynch Syndrome
Noralane M. Lindor,Gloria M. Petersen,Donald W. Hadley,Anita Y. Kinney,Susan Miesfeldt,Karen H. Lu,Patrick M. Lynch,Wylie Burke +7 more
TL;DR: Burke et al. as mentioned in this paper published an article in JAMA that set forth recommendations for care of individuals with an inherited predisposition to hereditary nonpolyposis colorectal cancer (HNPCC).
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