# Patients with Papillary Renal Cancer and Germline Duplication of MET Exons 5-21

## TL;DR

This paper reports a new genetic duplication in the MET gene linked to a rare kidney cancer syndrome, which may have implications for diagnosis and understanding of the disease.

## Contribution

The first description of a germline duplication in MET exons 5-21 in patients with HPRC-like features.

## Key findings

- Patients with clinical features of HPRC had a 101.4 kb duplication in the MET gene covering exons 5-21.
- The duplication is classified as a variant of uncertain significance but may represent an activating mutation.
- Further studies are needed to determine the duplication's pathogenicity and diagnostic relevance.

## Abstract

Hereditary papillary renal carcinoma (HPRC) is a rare monogenic hereditary disease in the group of hereditary cancer syndromes. Clinically, HPRC results in the development of multiple papillary renal cell carcinomas of the kidneys in young adults. HPRC is caused by point activating mutations in the MET gene encoding a transmembrane tyrosine kinase receptor. Until now, all detected germline mutations in HPRC patients were missense variants leading to a constitutive activation of the tyrosine kinase domain. We describe, for the first time, unrelated patients with clinical features similar to HPRC and without MET pathogenic missense variants but harboring an extended heterozygous duplication ~101.4 kb in length (chr7:116740252-116841718) in 7q31.2 determined using whole-genome sequencing (WGS). This duplication results in an additional copy of the MET gene fragment, including exons 5-21. The duplicated exons encode most of the receptor domains. According to the American College of Medical Genetics and Genomics (ACMG) criteria, this duplication is classified as variant of uncertain significance (VUS) at present, but it is not excluded that this duplication may represent an activating mutation. Perhaps, further segregation analysis and functional studies will allow us to more accurately resolve the pathogenicity and diagnostic significance of this germline CNV.