rs398124541

Variant names:

• chr17-17219187-GCTTT-G
• rs398124541
• NM_144997.7:c.890_893delAAAG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 16P and 4B. PVS1 PP5_Very_Strong BS2

The NM_144997.7(FLCN):​c.890_893delAAAG​(p.Glu297AlafsTer25) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000137 in 1,461,770 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: FLCN NM_144997.7 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 3.71
• Publications: 6 publications found

Genes affected

FLCN (HGNC:27310): (folliculin) This gene is located within the Smith-Magenis syndrome region on chromosome 17. Mutations in this gene are associated with Birt-Hogg-Dube syndrome, which is characterized by fibrofolliculomas, renal tumors, lung cysts, and pneumothorax. Alternative splicing of this gene results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

FLCN Gene-Disease associations (from GenCC):

• Birt-Hogg-Dube syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
• Birt-Hogg-Dube syndrome 1

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P, Ambry Genetics
• familial spontaneous pneumothorax

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Ambry Genetics
• renal carcinoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• colorectal cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000264187 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 17-17219187-GCTTT-G is Pathogenic according to our data. Variant chr17-17219187-GCTTT-G is described in ClinVar as Pathogenic. ClinVar VariationId is 96492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLCN	NM_144997.7	c.890_893delAAAG	p.Glu297AlafsTer25	frameshift_variant	Exon 9 of 14	ENST00000285071.9	NP_659434.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLCN	ENST00000285071.9	c.890_893delAAAG	p.Glu297AlafsTer25	frameshift_variant	Exon 9 of 14	1	NM_144997.7	ENSP00000285071.4
ENSG00000264187	ENST00000427497.3	n.149-137_149-134delAAAG		intron_variant	Intron 4 of 11	1		ENSP00000394249.3
FLCN	ENST00000577591.1	n.-88_-85delAAAG		upstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251428 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461770 Hom.: 0 AF XY: 0.00000963 AC XY: 7 AN XY: 727206

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53306

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000171 AC: 19 AN: 1112006

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Feb 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Apr 03, 2013

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 27, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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) -

Dec 16, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Birt-Hogg-Dube syndrome Pathogenic:3

Oct 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Jul 06, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

Jul 18, 2016

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

FLCN-related disorder Pathogenic:1

Sep 01, 2022

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Aug 02, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.7
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs398124541; hg19: chr17-17122501;