# Advancing the Landscape of Clinical Actionability in Von Hippel–Lindau Syndrome: An Evidence-Based Framework from the INT2GRATE Oncology Consortium

## TL;DR

This paper introduces a new framework and open-access portal to accurately assess genetic variants in Von Hippel–Lindau Syndrome, improving precision oncology and patient care.

## Contribution

The novel INT2GRATE variant evidence framework (VEF) integrates constitutional and tumor data to distinguish VHL-related conditions from sporadic tumors.

## Key findings

- The INT2GRATE VEF analyzed 2672 VHL variants to differentiate constitutional, sporadic, and allelic conditions.
- The open-access INT2GRATE Variant Portal was created to share germline VHL variant data and evidence.

## Abstract

In cancer syndromes, a precise assessment of variant actionability requires a comprehensive set of evidence to delineate the role of a variant in disease while effectively distinguishing it from potential differential diagnoses with similar cancer presentations and from sporadic occurrences. The INT2GRATE programs and the INT2GRATE Oncology Consortium address this challenge through an integrated analysis of constitutional and tumor data. Here, we present a novel variant evidence framework (VEF) for precision variant assessment in Von Hippel–Lindau Syndrome (VHL). The INT2GRATE VEF, applied to 2672 VHL variants, distinguishes constitutional, sporadic, VHL differential, and VHL allelic conditions. We also present the open-access INT2GRATE Variant Portal, a novel resource that provides a repository of the germline VHL variants and evidence, promoting data sharing, advancing precision oncology, and improving patient care.

Background/Objectives: An accurate evaluation of variant actionability is essential in cancer management. In Von Hippel–Lindau Syndrome (VHL), the interpretation of the germline variants is confounded by the presence of non-syndromic component tumors, such as clear cell renal cell carcinoma (ccRCC), hemangioblastoma, pheochromocytoma, and neuroendocrine tumors. These tumors frequently occur sporadically, without any association with VHL syndrome. The presence of these tumors in a patient with a germline VHL variant could lead to inaccurate attribution of these tumors to the germline variant and VHL syndrome. In our previous INT2GRATE (INTegrated INTerpretation of GeRmline And Tumor gEnomes) programs, we demonstrated that integrating tumor-derived and germline evidence offers a comprehensive approach for the accurate assessment of the germline variants in cancer syndromes. Methods/Results: Here, we present a novel INT2GRATE variant evidence framework (VEF) for evaluating the clinical actionability of the germline variants in VHL syndrome, offering an integrated approach that incorporates both constitutional and tumor data. We analyzed 2672 variants in the VHL gene and their associated tumors and clinical evidence to effectively distinguish between constitutional, sporadic, VHL differentials, and VHL allelic genetic conditions. The germline INT2GRATE variants, along with their comprehensive associated evidence, were made accessible in the first open-access INT2GRATE Variant data Portal. Conclusions: This novel and integrated approach to variant assessment and data sharing in hereditary cancer syndromes is essential in the clinical evaluation of genomic variants, advancing precision oncology, and improving patient care.