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

dbSNP: rs398124541

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	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	Birt-Hogg-Dube syndrome	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	2023-08-02	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 (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.
Invitae	RCV000239720	SCV000836092	pathogenic	Birt-Hogg-Dube syndrome	2023-11-09	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. Loss-of-function variants in FLCN are known to be pathogenic (PMID: 15852235). This variant is present in population databases (rs398124541, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with Birt-Hogg-Dub_x0001_e (BHD) syndrome, colorectal cancer, and/or renal cell cancer with pulmonary features (PMID: 18794106, 19785621, 27356891, 27470329, 27643397). It has also been observed to segregate with disease in related individuals. This variant is also known as c.1388_1391delAAAG. ClinVar contains an entry for this variant (Variation ID: 96492). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000082644	SCV001474014	pathogenic	not provided	2023-02-22	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.
PreventionGenetics, part of Exact Sciences	RCV003415852	SCV004118653	pathogenic	FLCN-related condition	2022-09-01	criteria provided, single submitter	clinical testing	The FLCN c.890_893delAAAG variant is predicted to result in a frameshift and premature protein termination (p.Glu297Alafs*25). In the literature, this variant is also referred to as c.1388_1391delAAAG (p.Glu297Alafs*321). This variant has been reported in individuals with Birt-Hogg-Dub syndrome (Kluger et al. 2009. PubMed ID: 19785621; Dow et al. 2016. PubMed ID: 27643397; Sprague et al. 2016. PubMed ID: 27470329). This variant, in the heterozygous state, was also reported in an individual who presented with isolated renal cell carcinoma and later developed pulmonary features (Patient 2, Woodward et al. 2008. PubMed ID: 18794106) and in another individual with colorectal cancer (Dobbins et al. 2016. PubMed ID: 27356891). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-17122501-GCTTT-G). Frameshift variants in FLCN are expected to be pathogenic. This variant is interpreted as pathogenic.
Myriad Genetics, Inc.	RCV000239720	SCV004188974	pathogenic	Birt-Hogg-Dube syndrome	2023-07-06	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000082644	SCV004219734	pathogenic	not provided	2021-12-16	criteria provided, single submitter	clinical testing	This frameshift variant alters the translational reading frame of the FLCN mRNA and causes the premature termination of FLCN protein synthesis. The frequency of this variant in the general population, 0.000018 (2/113764 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals/families with Birt-Hogg-Dube (BHD) syndrome (PMIDs: 19785621 (2010), 27470329 (2016), 27643397 (2016)) as well as an individual with renal cell carcinoma (RCC) (PMID: 18794106 (2008)), and an individual with colorectal cancer (PMID: 27356891 (2016)). Based on the available information, this variant is classified as pathogenic.