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ORIGINAL RESEARCH article

Front. Oncol.
Sec. Cancer Genetics
Volume 15 - 2025 | doi: 10.3389/fonc.2025.1455509

Reclassification of Variants of Uncertain Significance by Race, Ethnicity, and Ancestry for Patients at Risk for Breast Cancer

Provisionally accepted
Versha Pleasant Versha Pleasant 1*Jordyn Boggan Jordyn Boggan 1Blair Richards Blair Richards 1Kara J. Milliron Kara J. Milliron 1Kristen S. Purrington Kristen S. Purrington 2Michael Steven Simon Michael Steven Simon 2Sofia Diana Merajver Sofia Diana Merajver 1
  • 1 University of Michigan, Ann Arbor, United States
  • 2 Barbara Ann Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, Michigan, United States

The final, formatted version of the article will be published soon.

    Introduction: Although most variants of uncertain significance (VUS) are downgraded, it is unclear if this applies to those of non-European ancestry. This study examines the time to and type of VUS reclassification among a diverse cohort at risk for breast cancer. Methods: A multi-center retrospective analysis examined people assigned female at birth (AFAB) who underwent genetic testing from 2013-2021 with VUS in: ATM, BARD1, BRCA1/2, CDH1, CHEK2, NF1, PALB2, PTEN, RAD51C/D, STK11, and/or TP53. Demographic data was collected (including race, ethnicity, and ancestry (REA)), as well as time to and type of reclassification. Frequency data, univariable, and multivariable analyses were performed (p<0.05 was considered statistically significant). Results: 932 participants had a total of 1,032 VUS (905 unique mutations), with 20% who had reclassification of their results. The proportion of reclassified VUS among the largest represented groups were 19%, 23%, and 27% for White, Black, and Asian people, respectively. REA was not associated with VUS reclassification (p=0.25). The mean time to VUS reclassification was 2.8 years and was not significantly associated with REA (p=0.16). Most VUS were downgraded to benign/likely benign (n=187, 92%). Discussion: Our findings demonstrate that race, ethnicity, and ancestry are not significantly associated with length of time to VUS reclassification or type of reclassification for AFAB people who are at risk for breast cancer. This study allows for improved and more equitable genetic counseling. It may also provide more reassurance to those groups that may have a higher likelihood of VUS results.

    Keywords: breast cancer, cancer genetics, variants of uncertain significance, race, ethnicity, ancestry, genetic testing ATM, bard1

    Received: 27 Jun 2024; Accepted: 13 Jan 2025.

    Copyright: © 2025 Pleasant, Boggan, Richards, Milliron, Purrington, Simon and Merajver. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Versha Pleasant, University of Michigan, Ann Arbor, United States

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.