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ClinGen guidance for use of the PP1/BS4 co-segregation and PP4 phenotype specificity criteria for sequence variant pathogenicity classification.
Biesecker, Leslie G; Byrne, Alicia B; Harrison, Steven M; Pesaran, Tina; Schäffer, Alejandro A; Shirts, Brian H; Tavtigian, Sean V; Rehm, Heidi L.
Afiliación
  • Biesecker LG; Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address: lesb@mail.nih.gov.
  • Byrne AB; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Harrison SM; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Ambry Genetics, Aliso Viejo, CA, USA.
  • Pesaran T; Ambry Genetics, Aliso Viejo, CA, USA.
  • Schäffer AA; Cancer Data Science Laboratory, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Shirts BH; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA.
  • Tavtigian SV; Department of Oncological Sciences, University of Utah School of Medicine and Huntsman Cancer Institute at the University of Utah, Salt Lake City, UT, USA.
  • Rehm HL; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Am J Hum Genet ; 111(1): 24-38, 2024 01 04.
Article en En | MEDLINE | ID: mdl-38103548
ABSTRACT
The 2015 American College of Medical Genetics and Genomics and the Association for Molecular Pathology variant classification publication established a standard employed internationally to guide laboratories in variant assessment. Those recommendations included both pathogenic (PP1) and benign (BS4) criteria for evaluating the inheritance patterns of variants, but details of how to apply those criteria at appropriate evidence levels were sparse. Several publications have since attempted to provide additional guidance, but anecdotally, this issue is still challenging. Additionally, it is not clear that those prior efforts fully distinguished disease-gene identification considerations from variant pathogenicity considerations nor did they address autosomal-recessive and X-linked inheritance. Here, we have taken a mixed inductive and deductive approach to this problem using real diseases as examples. We have developed a practical heuristic for genetic co-segregation evidence and have also determined that the specific phenotype criterion (PP4) is inseparably coupled to the co-segregation criterion. We have also determined that negative evidence at one locus constitutes positive evidence for other loci for disorders with locus heterogeneity. Finally, we provide a points-based system for evaluating phenotype and co-segregation as evidence types to support or refute a locus and show how that can be integrated into the Bayesian framework now used for variant classification and consistent with the 2015 guidelines.
Asunto(s)

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Variación Genética / Pruebas Genéticas Límite: Humans Idioma: En Revista: Am J Hum Genet Año: 2024 Tipo del documento: Article

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Variación Genética / Pruebas Genéticas Límite: Humans Idioma: En Revista: Am J Hum Genet Año: 2024 Tipo del documento: Article