Author:
Parsons Michael T.,de la Hoya Miguel,Richardson Marcy E.,Tudini Emma,Anderson Michael,Berkofsky-Fessler Windy,Caputo Sandrine M.,Chan Raymond C.,Cline Melissa C.,Feng Bing-Jian,Fortuno Cristina,Gomez-Garcia Encarna,Hadler Johanna,Hiraki Susan,Holdren Megan,Houdayer Claude,Hruska Kathleen,James Paul,Karam Rachid,Leong Huei San,Martins Alexandra,Mensenkamp Arjen R.,Monteiro Alvaro N.,Nathan Vaishnavi,O’Connor Robert,Pedersen Inge Sokilde,Pesaran Tina,Radice Paolo,Schmidt Gunnar,Southey Melissa,Tavtigian Sean,Thompson Bryony A.,Toland Amanda E.,Turnbull Clare,Vogel Maartje J.,Weyandt Jamie,Wiggins George A.R.,Zec Lauren,Couch Fergus J.,Walker Logan C.,Vreeswijk Maaike P. G.,Goldgar David E.,Spurdle Amanda B.
Abstract
AbstractThe ENIGMA research consortium (https://enigmaconsortium.org/) develops and applies methods to determine clinical significance of variants in Hereditary Breast and Ovarian Cancer genes. An ENIGMABRCA1/2classification sub-group, originally formed in 2016 as a ClinGen external expert panel, evolved into a ClinGen internal Variant Curation Expert Panel (VCEP) to align with Federal Drug Administration recognized processes for ClinVar contributions.The VCEP reviewed American College of Medical Genetics/Association of Molecular Pathology (ACMG/AMP) classification criteria for relevance to interpretingBRCA1andBRCA2variants. Statistical methods were used to calibrate evidence strength for different data types. Pilot specifications were tested on 40 variants, and documentation revised for clarity and ease-of-use.The original criterion descriptions for 13 evidence codes were considered non-applicable or overlapping with other criteria. Scenario of use was extended or re-purposed for eight codes. Extensive analysis and/or data review informed specification descriptions and weights for all codes. Specifications were applied to pilot variants with pre-existing ClinVar classification as follows: 13 Uncertain Significance or Conflicting, 14 Pathogenic and/or Likely Pathogenic, and 13 Benign and/or Likely Benign. Review resolved classification for 11/13 Uncertain Significance or Conflicting variants, and retained or improved confidence in classification for the remaining variants.Alignment of pre-existing ENIGMA research classification processes with ACMG/AMP classification guidelines highlighted several gaps in both the research processes and the baseline ACMG/AMP criteria. Calibration of evidence types was key to justify utility and strength of different evidence types for gene-specific application. The gene-specific criteria demonstrated value for improving ACMG/AMP-aligned classification ofBRCA1andBRCA2variants.
Publisher
Cold Spring Harbor Laboratory