ClinVar

Description

The c.890_893delAAAG pathogenic mutation, located in coding exon 6 of the FLCN gene, results from a deletion of 4 nucleotides at nucleotide positions 890 to 893, causing a translational frameshift with a predicted alternate stop codon (p.E297Afs*25). This mutation was reported in a 25-year-old female with renal cell carcinoma (Woodward ER et al. Clin. Cancer Res., 2008 Sep;14:5925-30) and has also been reported in a Birt-Hogg-Dubé syndrome (BHDS) kindred, that presented with extensive multi-organ system involvement, including fibrofolliculomas, acrochordons, oral papules, lentigines, lipomas, lung cysts, thyroid nodules, cafe-au-lait spots, kidney cysts, rectal papules, endobrachyoesphagus, pneumothorax, colonic adenomatous polyps and atypical mole syndrome (Kluger N et al. Br. J. Dermatol., 2010 Mar;162:527-37). A case report described an 8-year-old boy found to carry this alteration, who presented with nevus comedonicus-like lesion present since birth and had family history of BHDS in his mother, who had been affected with numerous fibrofolliculomas on the face, multiple lung cysts and had a history of spontaneous pneumothorax (Sprague J et al. Pediatr Dermatol, 2016 Jul [Epub ahead of print]). This alteration has also been found in one patient from a cohort of patients with early-onset (at or before 55 years-old) familial (including at least one first degree relative) colorectal cancer, who had no personal or family history of renal cancer (Dobbins SE et al. Fam. Cancer, 2016 Jun [Epub ahead of print]). Note that this alteration is also referred to as c.1388_1391delAAAG and c.1345_1348delAAAG in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.