loading page

Multiple Endocrine Neoplasia Type 2 (MEN2) and RET Specific Modifications of the ACMG/AMP Variant Classification Guidelines and Impact on the MEN2 RET Database
  • +3
  • Rebecca L. Margraf,
  • Rachel Z. Alexander,
  • Makenzie L. Fulmer,
  • Christine Miller,
  • Elena Coupal,
  • Rong Mao
Rebecca L. Margraf
ARUP Institute for Clinical and Experimental Pathology

Corresponding Author:[email protected]

Author Profile
Rachel Z. Alexander
OhioHealth
Author Profile
Makenzie L. Fulmer
ARUP Institute for Clinical and Experimental Pathology
Author Profile
Christine Miller
ARUP Institute for Clinical and Experimental Pathology
Author Profile
Elena Coupal
ARUP Institute for Clinical and Experimental Pathology
Author Profile
Rong Mao
ARUP Institute for Clinical and Experimental Pathology
Author Profile

Abstract

The Multiple Endocrine Neoplasia type 2 (MEN2) RET proto-oncogene database, originally published in 2008, is a comprehensive repository of all publicly available RET gene variations associated with MEN2 syndromes. The variant-specific genotype/phenotype information, age of earliest reported medullary thyroid carcinoma onset, and relevant references with a brief summary of findings are cataloged. The ACMG/AMP 2015 consensus statement on variant classification was modified specifically for MEN2 syndromes and RET variants using ClinGen sequence variant interpretation working group recommendations and ClinGen expert panel manuscripts, as well as manuscripts from the American Thyroid Association Guidelines Task Force on Medullary Thyroid Carcinoma and other MEN2 RET literature. The classifications for the 166 single unique variants in the MEN2 RET database were reanalyzed using the MEN2 RET specifically modified ACMG/AMP classification guidelines. Applying these guidelines added two new variant classifications to the database (likely benign and likely pathogenic) and resulted in clinically significant classification changes ( e.g. from pathogenic to uncertain) in 16.9% (28/166) of the original variants. Of those clinically significant changes, the highest percentage of changes, 46.4% (13/28), were changes from uncertain to benign or likely benign. The modified ACMG/AMP criteria with MEN2 RET specifications will optimize and standardize RET variant classifications.
20 Apr 2022Submitted to Human Mutation
21 Apr 2022Submission Checks Completed
21 Apr 2022Assigned to Editor
23 Aug 2022Reviewer(s) Assigned
31 Aug 2022Review(s) Completed, Editorial Evaluation Pending
31 Aug 2022Editorial Decision: Revise Major
21 Sep 20221st Revision Received
22 Sep 2022Submission Checks Completed
22 Sep 2022Assigned to Editor
22 Sep 2022Review(s) Completed, Editorial Evaluation Pending
22 Sep 2022Reviewer(s) Assigned
04 Oct 2022Editorial Decision: Accept
Dec 2022Published in Human Mutation volume 43 issue 12 on pages 1780-1794. 10.1002/humu.24486