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Colorectal cancer (CRC) has been explored for involvement of the tumor suppressor FLCN, best known for Birt-Hogg-Dubé syndrome. In 35 sporadic CRC primary tumors and cell lines, a somatic FLCN missense substitution Arg392Gly and a germline c.959G>A (p.Arg320Gln) variant, absent in 199 control alleles, were identified, consistent with a two‐hit tumorigenic mechanism (PMID:14627671). Neither promoter hypermethylation nor epigenetic silencing of FLCN was detected in 20 primary tumors, suggesting that mutation is the principal inactivation route (PMID:14627671). No familial segregation or recurrence of FLCN variants was observed beyond these isolated cases, limiting statistical power and replication. Functional studies directly linking FLCN inactivation to CRC phenotype are lacking, though mechanistic parallels can be drawn from renal cancer contexts. Overall, evidence for a causal role of FLCN in colorectal cancer remains Limited. Key Take-home: while FLCN mutations occur sporadically in CRC, routine screening for FLCN outside hereditary BHD syndrome is not currently supported by robust clinical validity.
Gene–Disease AssociationLimitedSingle somatic FLCN p.Arg392Gly and one germline p.Arg320Gln in two CRC cases; no segregation ([PMID:14627671]) Genetic EvidenceLimitedOne somatic missense and one germline missense variant in 35 CRCs, absent in controls, no familial segregation ([PMID:14627671]) Functional EvidenceLimitedNo evidence of promoter hypermethylation or epigenetic silencing in CRC tumors ([PMID:14627671]) |