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\begin{document}

\title{Multiple Endocrine Neoplasia Type 2 (MEN2) and RET Specific
Modifications of the ACMG/AMP Variant Classification Guidelines and
Impact on the MEN2 RET Database}



\author[1]{Rebecca L. Margraf}%
\author[2]{Rachel Z. Alexander}%
\author[1]{Makenzie L. Fulmer}%
\author[1]{Christine Miller}%
\author[1]{Elena Coupal}%
\author[1]{Rong Mao}%
\affil[1]{ARUP Institute for Clinical and Experimental Pathology}%
\affil[2]{OhioHealth}%


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  \date{May 26, 2024}


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\begin{abstract}
The Multiple Endocrine Neoplasia type 2 (MEN2) \emph{RET} proto-oncogene
database, originally published in 2008, is a comprehensive repository of
all publicly available \emph{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 \emph{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 \emph{RET} literature. The classifications for
the 166 single unique variants in the MEN2 \emph{RET} database were
reanalyzed using the MEN2 \emph{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 ( \emph{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 \emph{RET} specifications will optimize and standardize
\emph{RET} variant classifications.%
\end{abstract}%



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\textbf{Hosted file}

\verb`2022 MEN2 database HuMut v3.docx`  available at \url{https://authorea.com/users/477831/articles/566249-multiple-endocrine-neoplasia-type-2-men2-and-ret-specific-modifications-of-the-acmg-amp-variant-classification-guidelines-and-impact-on-the-men2-ret-database}

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