ClinVar Miner

Submissions for variant NM_144997.7(FLCN):c.890_893del (p.Glu297fs) (rs398124541)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000082644 SCV000114686 pathogenic not provided 2013-04-03 criteria provided, single submitter clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000239720 SCV000298064 pathogenic Multiple fibrofolliculomas 2016-07-18 criteria provided, single submitter clinical testing
GeneDx RCV000082644 SCV000565006 pathogenic not provided 2021-01-27 criteria provided, single submitter clinical testing Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Identified in patients with Birt-Hogg-Dub syndrome in published literature (Kluger 2010, Dow 2016, Sprague 2016); This variant is associated with the following publications: (PMID: 19785621, 27470329, 27356891, 29138412, 27643397, 18794106)
Ambry Genetics RCV000492401 SCV000580734 pathogenic Hereditary cancer-predisposing syndrome 2019-10-29 criteria provided, single submitter clinical testing 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. 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.
Invitae RCV000239720 SCV000836092 pathogenic Multiple fibrofolliculomas 2020-10-20 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu297Alafs*25) in the FLCN gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs398124541, ExAC 0.001%). This variant has been observed to segregate with Birt-Hogg-Dub_x0001_e (BHD) syndrome in several families (PMID: 27643397, 27470329, 19785621). Additionally, this variant has been reported in an individual affected with isolated renal cell cancer, who later presented with pulmonary features (PMID: 18794106), and an individual affected with colorectal cancer (PMID: 27356891). This variant is also known as c.1388_1391delAAAG in the literature. ClinVar contains an entry for this variant (Variation ID: 96492). Loss-of-function variants in FLCN are known to be pathogenic (PMID: 15852235). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001287339 SCV001474014 pathogenic none provided 2019-11-24 criteria provided, single submitter clinical testing The FLCN c.890_893delAAAG; p.Glu297fs variant (rs398124541), also known as 1388_1391delAAAG, is reported in individuals with Birt-Hogg-Dube syndrome (Dow 2016, Kluger 2010, Sprague 2016, Woodward 2008) and classified as pathogenic in ClinVar (Variation ID: 96492). This variant is only observed on 2 alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting 4 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Dow E et al. Renal angiomyolipoma in Birt-Hogg-Dube syndrome: A case study supporting overlap with tuberous sclerosis complex. Am J Med Genet A. 2016 Dec;170(12):3323-3326. Kluger N et al. Birt-Hogg-Dube syndrome: clinical and genetic studies of 10 French families. Br J Dermatol. 2010 Mar;162(3):527-37. Sprague J et al. Birt-Hogg-Dube Syndrome Presenting as a Nevus Comedonicus-Like Lesion in an 8-Year-Old Boy. Pediatr Dermatol. 2016 Sep;33(5):e294-5. Woodward ER et al. Familial non-VHL clear cell (conventional) renal cell carcinoma: clinical features, segregation analysis, and mutation analysis of FLCN. Clin Cancer Res. 2008 Sep 15;14(18):5925-30.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.