Abstract ES3-1: Reclassifying VUS: New techniques can solve the puzzle once and for all

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Abstract Over the last 10 years, the scale of genetic testing for cancer predisposition has increased dramatically. Two simple facts drive this trend: (1) improving test technology has reduced the costs while increasing clinical yield, and (2) medical and surgical approaches to risk reduction can add years to the lives of carriers of pathogenic variants if these individuals are identified through cascade testing before they develop a metastatic tumor. Initial outcomes from this genetic testing fall into one of three categories: a pathogenic sequence variant(s) is found, no reportable sequence variant(s) is found, or a variant(s) of uncertain significance (VUS) is found. The observation and reporting of VUS remains problematic because (among other reasons) the inherent informational uncertainty can raise patient anxiety, and medical over-interpretation of VUS can lead to over-treatment of healthy individuals who carry that sequence variant. In 2008, an International Agency for Research on Cancer (IARC) Working Group on unclassified sequence variants published guidelines for classification of VUS in cancer susceptibility genes. Those guidelines were fundamentally quantitative, but were not efficient enough to keep up with the rate of VUS identification since then. In 2015, the American College of Medical Genetics (ACMG) published guidelines for classification of sequence variants in all Mendelian disease susceptibility genes. While the ACMG guidelines were qualitative, they had the advantage of being more efficient than the IARC guidelines. In 2018, we demonstrated that the qualitative ACMG guidelines are compatible with a quantitative Bayesian interpretation. Although the Bayesian re-interpretation validated the ACMG guidelines, it was not appropriate for day-to-day use because it requires users actually to execute the math of Bayes’ rule. In 2020, we derived a points-system for VUS evaluation from the Bayesian re-interpretation of the ACMG guidelines. The points system provides a number of advantages, including: (1) while quantitative, it faithfully reflects the ACMG qualitative guidelines; (2) using the points system requires no more than addition and subtraction, so there is no math barrier; and (3) it provides a route to calibrating ACMG “evidence criteria” (heretofore referred to as “data types”), which will become central to solving the VUS puzzle. Over the last few years, three additional strands are converging towards acceleration of VUS classification. The first strand is a community drive towards more accurate computational tools for VUS evaluation. In ACMG parlance, this data type is limited to “Supporting” evidence for or against pathogenicity, but will likely be shown to generate stronger (at least “Moderate”) evidence. The second strand is development of high-throughput functional assays. These assays can now be used to evaluate all possible missense substitutions encoded by smaller genes, and at least the key functional domains of large genes. In principle, these assays can generate “Strong” evidence for or against pathogenicity. The third strand is a clearer understanding of standards that need to be met when calibrating various data types toward variant classification - a direct benefit of the quantitative Bayesian re-interpretation of the ACMG guidelines. In the points system for VUS evaluation, Moderate evidence provides +/- 2 points, Strong evidence provides +/- 4 points, and the threshold for re-classifying a VUS as Likely Pathogenic is +6 points. Hence a large fraction of the VUS that are actually pathogenic may be classified as Likely Pathogenic through a combination of well calibrated computational data, well calibrated functional assay data, and minimal patient or population observational data. Hence a mantra for the next few years of “2 + 4 = 6. Better be sure that the 2 is correct, the 4 is correct, and addition is the correct operator”. Citation Format: S Tavtigian. Reclassifying VUS: New techniques can solve the puzzle once and for all [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr ES3-1.