Actionability Classification of Variants of Unknown Significance Correlates With Functional Effect

Authors

Amber Johnson
Patrick Kwok-Shing Ng
Michael Kahle
Julia Castillo
Bianca Amador
Yujia Wang
Jia Zeng
Vijaykumar Holla
Thuy Vu
Fei Su
Sun-Hee Kim
Tara Conway
Xianli Jiang
Ken Chen
Kenna R Mills Shaw
Timothy A Yap
Jordi Rodon
Gordon B Mills
Funda Meric-Bernstam

Publication Date

7-15-2023

Journal

NPJ Precision Oncology

Abstract

Genomically-informed therapy requires consideration of the functional impact of genomic alterations on protein expression and/or function. However, a substantial number of variants are of unknown significance (VUS). The MD Anderson Precision Oncology Decision Support (PODS) team developed an actionability classification scheme that categorizes VUS as either "Unknown" or "Potentially" actionable based on their location within functional domains and/or proximity to known oncogenic variants. We then compared PODS VUS actionability classification with results from a functional genomics platform consisting of mutant generation and cell viability assays. 106 (24%) of 438 VUS in 20 actionable genes were classified as oncogenic in functional assays. Variants categorized by PODS as Potentially actionable (N = 204) were more likely to be oncogenic than those categorized as Unknown (N = 230) (37% vs 13%, p = 4.08e-09). Our results demonstrate that rule-based actionability classification of VUS can identify patients more likely to have actionable variants for consideration with genomically-matched therapy.

Keywords

Tumour biomarkers, Clinical genetics

DOI

10.1038/s41698-023-00420-w

PMID

37454202

PMCID

PMC10349825

PubMedCentral® Posted Date

7-15-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes