Submissions for variant NM_144997.7(FLCN):c.250-2A>G

dbSNP: rs398124533

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000082633	SCV000114675	pathogenic	not provided	2012-08-02	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000239670	SCV000298040	pathogenic	Birt-Hogg-Dube syndrome	2016-07-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000082633	SCV000321650	pathogenic	not provided	2023-01-31	criteria provided, single submitter	clinical testing	Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown; Deletions involving coding exons of this gene are a known mechanism of disease (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19802896, 29357828, 18234728, 25610687, 21937013, 25525159, 31958439, 34654685)
Ambry Genetics	RCV000492149	SCV000580730	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-23	criteria provided, single submitter	clinical testing	The c.250-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 2 in the FLCN gene. This alteration was previously identified in 13 individuals from four unrelated families affected with perifollicular fibromas, trichodiscomas, renal tumors, lung cysts and spontaneous pneumothorax (Toro J et al. J Med Genet. 2008 Jun;45(6):321-31). This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with FLCN-related disease (Ambry internal data). RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000239670	SCV000632865	pathogenic	Birt-Hogg-Dube syndrome	2024-10-29	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 4 of the FLCN gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs398124533, gnomAD 0.0009%). Disruption of this splice site has been observed in individuals with Birt-Hogg-Dubé syndrome (PMID: 18234728). This variant is also known as IVS4-2A>G. ClinVar contains an entry for this variant (Variation ID: 96481). Studies have shown that disruption of this splice site results in activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (internal data). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000239670	SCV002571040	pathogenic	Birt-Hogg-Dube syndrome	2022-07-14	criteria provided, single submitter	clinical testing	Variant summary: FLCN c.250-2A>G, also referred to as IVS4-2A>G in the literature, is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251292 control chromosomes (gnomAD). c.250-2A>G has been reported in the literature in many individuals from multiple unrelated families affected with Birt-Hogg-Dube Syndrome (e.g. Toro_2008, Mikesell_2014, Sattler_2020). These data indicate that the variant is very likely to be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005003458	SCV002783339	pathogenic	Familial spontaneous pneumothorax; Nonpapillary renal cell carcinoma; Colorectal cancer; Birt-Hogg-Dube syndrome 1	2024-06-01	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000239670	SCV003806639	likely pathogenic	Birt-Hogg-Dube syndrome	2023-01-11	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.
Baylor Genetics	RCV000239670	SCV003836247	pathogenic	Birt-Hogg-Dube syndrome	2022-02-22	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003421978	SCV004106650	pathogenic	FLCN-related disorder	2023-05-04	criteria provided, single submitter	clinical testing	The FLCN c.250-2A>G variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant is alternatively referred to as IVS4-2A>G in the literature. This variant was reported in individuals with Birt-Hogg-Dubé syndrome (Table 1, Toro et al. 2008. PubMed ID: 18234728; Figure 2, Sattler et al. 2020. PubMed ID: 31958439; Truong et al. 2021. PubMed ID: 34654685). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-17129638-T-C). It is interpreted as likely pathogenic and pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/96481/). Variants that disrupt the consensus splice acceptor site in FLCN are expected to be pathogenic. This variant is interpreted as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000082633	SCV004219715	pathogenic	not provided	2023-07-08	criteria provided, single submitter	clinical testing	The FLCN c.250-2A>G variant disrupts a canonical splice-acceptor site and interferes with normal FLCN mRNA splicing. This variant has been reported in the published literature in several affected individuals and families with Birt-Hogg-Dubé syndrome (PMIDs: 18234728 (2008), 31958439 (2020), and 35639097 (2022)). It has also been reported in early onset renal cell carcinoma (PMID: 34654685 (2021)) and rhabdomyoma (PMID: 25610687 (2014)). Based on the available information, this variant is classified as pathogenic.
OMIM	RCV000239670	SCV000023701	pathogenic	Birt-Hogg-Dube syndrome	2009-09-01	no assertion criteria provided	literature only