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Inherited susceptibility to renal cell carcinoma (RCC) is associated with several predisposing genes, which can be detected by multigene panel testing. Germline pathogenic variants are found in approximately 6% of RCC. This study aims to determine the prevalence of these variants in Filipino RCC patients using next-generation sequencing.
A total of 29 participants diagnosed with RCC between January 2017 to December 2022 at St. Luke's Medical Center-Quezon City were eligible for germline genetic testing for the following genes: BAP1, CDC73, CDKN1C, DICER1, DIS3L2, EPCAM, FH, FLCN, GPC3, MET, MLH1, MSH2, MSH6, PMS2, PTEN, REST, SDHB, SDHC, SMARCA4, SMARCB1, TP53, TSC1, TSC2, VHL, and WT1.
The median age of diagnosis was 58; majority of patients were females (51%), with stage I disease (69%), and clear cell histology (83%). Variants of uncertain significance (VUS) in several genes were found in four (14%) patients. Of these patients, one had a papillary subtype with a VUS result in the FH gene, which is associated with hereditary leiomyomatosis and renal cell cancer (HLRCC), and in the REST gene, which is associated with Wilms tumor. The VUS in the FH gene, namely c.1268T>G (p.Leu423Arg), and in the REST gene, namely c.527A>G (Hp.His176Arg), were subject to advanced modeling of protein sequence and biophysical properties, which indicate that these missense variants are expected to be disruptive.
No clinically relevant germline pathogenic variants in RCC predisposed genes were detected in our study. Furthermore, there is insufficient data on the functional and clinical implications of having VUS but reclassification of these variants in the future should be awaited as this may imply clinical consequences like risk-reducing surgery, change in prognosis and treatment, and emotional impact. Our study underscores the importance of building an updated national RCC genetic registry and providing familial VUS testing to allow for future variant reclassification.