Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
Germline variants in CDKN2B, encoding the p15^INK4b^ cyclin-dependent kinase inhibitor, have been implicated in inherited renal cell carcinoma (PMID:35422439; PMID:25873077). The association with renal cell carcinoma is supported by multiple independent probands, segregation in a familial kindred, and functional studies demonstrating loss of tumor suppressor activity.
Autosomal dominant inheritance is established by exome resequencing of a familial renal carcinoma kindred in which a heterozygous CDKN2B nonsense variant co-segregated with disease (PMID:25873077). Targeted resequencing of 82 individuals with features of inherited RCC identified three additional missense variants—c.256G>A (p.Asp86Asn), c.68C>A (p.Ala23Glu) and c.118C>A (p.Pro40Thr)—in unrelated probands, yielding a total of five affected individuals across four kindreds (PMID:25873077; PMID:35422439).
A de novo germline 9p21.3 microdeletion encompassing CDKN2A and CDKN2B was reported in a young woman with six primary cancers, including early-onset renal cell carcinoma, supporting a contiguous gene deletion syndrome with additive risk beyond single-gene haploinsufficiency (PMID:35422439).
Functional characterization of the p.Asp86Asn, p.Ala23Glu and p.Pro40Thr missense substitutions revealed impaired CDKN2B-mediated inhibition of cell proliferation in renal carcinoma cell lines, consistent with loss-of-function and haploinsufficiency as the pathogenic mechanism (PMID:25873077).
No large-scale case–control studies have identified frequent germline CDKN2B mutations in unselected RCC cohorts, underscoring the rarity but high penetrance of these variants. Experimental and familial linkage data converge on a model in which CDKN2B haploinsufficiency disrupts cell-cycle control, predisposing to renal tumorigenesis.
Key Take-home: Germline CDKN2B loss-of-function variants confer autosomal dominant predisposition to renal cell carcinoma, warranting inclusion of CDKN2B in genetic testing panels for familial and early-onset RCC.
Gene–Disease AssociationStrongFive probands across four kindreds with germline CDKN2B variants, segregation in one family, and concordant functional impairment Genetic EvidenceModerateOne family with a segregating nonsense variant and three unrelated missense loss‐of‐function probands plus a de novo deletion case Functional EvidenceModerateIn vitro assays demonstrate impaired proliferation suppression for multiple CDKN2B missense variants |