Submissions for variant NM_144997.7(FLCN):c.1062+2T>G

dbSNP: rs886039370

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000254745	SCV000321659	pathogenic	not provided	2022-04-22	criteria provided, single submitter	clinical testing	Canonical splice site variant demonstrated to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease (Rossing 2017); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 15852235, 26659639, 20522427, 18234728, 17133269, 25519458, 29720200, 29357828, 27734835)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000812531	SCV000952848	pathogenic	Birt-Hogg-Dube syndrome	2024-09-16	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 9 of the FLCN gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in FLCN are known to be pathogenic (PMID: 15852235). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Birt-Hogg-Dubé syndrome (PMID: 15852235, 19802896, 27734835). It is commonly reported in individuals of Danish ancestry (PMID: 15852235, 19802896, 27734835). This variant is also known as IVS9+2T>G. ClinVar contains an entry for this variant (Variation ID: 265154). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 27734835). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV001009818	SCV001169932	pathogenic	Hereditary cancer-predisposing syndrome	2024-10-14	criteria provided, single submitter	clinical testing	The c.1062+2T>G intronic pathogenic mutation results from a T to G substitution two nucleotides after coding exon 6 in the FLCN gene. This mutation has been detected in numerous individuals meeting clinical diagnostic criteria for Birt-Hogg-Dube syndrome (BHD) (Schmidt LS et al. Am J Hum Genet. 2005 Jun;76(6):1023-33; Gad S et al. Br J Cancer. 2007 Jan 29;96(2):336-40; Toro JR et al. J Med Genet. 2008 Jun;45(6):321-31; Benusiglio PR et al. Orphanet J Rare Dis. 2014 Oct 29;9:163; Whitworth J et al. JAMA Oncol. 2016 Mar;2(3):373-9; Rossing M et al. J Hum Genet. 2017 Feb;62(2):151-157). While this mutation has been identified in BHD patients of various ethnicities, it has been reported to be especially prevalent in the Danish population and haplotype analysis revealed that it is a Danish founder mutation (Rossing M et al. J Hum Genet. 2017 Feb;62(2):151-157). Finally, a mini-gene splicing assay has shown that this mutation causes aberrant splicing (Rossing M et al. J Hum Genet. 2017 Feb;62(2):151-157). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000254745	SCV002551341	pathogenic	not provided	2025-03-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002479990	SCV002792265	pathogenic	Birt-Hogg-Dube syndrome; Familial spontaneous pneumothorax; 17p11.2 microduplication syndrome; Nonpapillary renal cell carcinoma; Colorectal cancer	2022-03-26	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000254745	SCV004227673	pathogenic	not provided	2023-02-02	criteria provided, single submitter	clinical testing	PP1, PP4, PM2, PVS1