Renal cell carcinoma typically develops sporadically, but it is estimated that 5-8% of all renal cell cancers occur due to a hereditary predisposition (Kallinikas et al., 2017; Czarniecki et al., 2018). Hereditary cancer predisposition syndromes associated with renal cell cancer (RCC) include: Von Hippel-Lindau, hereditary papillary renal cell carcinoma (HPRCC), Birt-Hogg-Dube syndrome, hereditary leiomyomatosis and renal cell carcinoma (HLRCC), succinate dehydrogenase deficiency, tuberous sclerosis complex, and Cowden syndrome (Bratslavsky et al., 2021). Additionally, upper tract urothelial carcinomas (most commonly transitional carcinomas of the ureter and renal pelvis) have been associated with Lynch syndrome (Kallinikas et al., 2017; Stratton et al., 2016). There is emerging evidence that inherited pathogenic/likely pathogenic (P/LP) variants in the BAP1, DICER1 and MITF are also associated with predisposition to RCC (Czarniecki et al., 2018; Smith et al. 2021).

Identification of a hereditary component has direct implications for management and surveillance of an individual patient, as well as their family members. Specific screening and management recommendations differ based on the specific syndrome identified, and tumor surveillance after confirmatory genetic testing has been shown to improve outcomes following positive testing (Stratton et al., 2016). 

The presence of bilateral tumors, multifocal tumors, or cancers diagnosed at younger ages (<50 years) should prompt further evaluation for hereditary cancer syndromes (Maher, 2018; Powles et al., 2024), though not all patients with inherited predispositions have this history (Nguyen et al., 2023). The subclassification of renal cell cancer is based on histological type and molecular pathogenesis (Menko et al., 2016). Often, renal imaging findings are identified that raise suspicion for a particular hereditary syndrome. For example, Von Hippel-Lindau is characterized by multiple renal cysts lined by clear cells. Clear cell RCC is the most common cancer type in people with VHL. Histological type can also be used to direct germline genetic testing (Peng and Chen, 2018). Tumors that arise from oncocytic lesions are typically associated with Birt-Hogg-Dube syndrome due to FLCN P/LP variants. Type 1 papillary RCC is characteristic of HPRCC, and type 2 papillary RCC is characteristic of HLRCC (Czarniecki et al., 2018). Extra-renal manifestations are also able to help distinguish various hereditary renal cancer syndromes, such as soft tissue and uterine leiomyomas in HLRCC, cortical tubers in people with tuberous sclerosis, and paragangliomas/pheochromocytomas in those with succinate dehydrogenase deficiency.

While some laboratories offer multi-gene panels that include a number of genes associated with inherited renal cancer syndromes, it is rare for every gene to be indicated for a particular patient or family as there is relatively little overlap in clinical presentation between these conditions. Some panels include genes with no confirmed association with hereditary renal cancer, or more newly described genes that are not clinically actionable when a P/LP variant is identified. Even within well-described genes, variants of unknown significance (VUS) present a clinical challenge. Limiting evaluation to genes with established clinical validity and relevance to a patient’s personal/family history reduces both the risk of uncertain results and the possibility for overtreatment (Tung et al., 2024). Correlating panel gene make-up to personal/family history phenotype also allows for more precise cancer risk estimates (Tung et al., 2024). Consensus guidelines for referral to genetic specialists based on histology and other clinical features, as well as testing strategies, have been published (Bratslavskly, et al., 2021). When a condition associated with hereditary renal cancer is suspected, it is most appropriate to target testing based on the specific presentation in the patient and family.