ClinVar Miner

Submissions for variant NM_144997.7(FLCN):c.1432+1G>A (rs755959303)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000239711 SCV000298084 pathogenic Multiple fibrofolliculomas 2016-07-18 criteria provided, single submitter clinical testing
GeneDx RCV000254996 SCV000321668 likely pathogenic not provided 2019-11-26 criteria provided, single submitter clinical testing Canonical splice site variant predicted to result in an in-frame deletion of a critical region: C-terminal region that interacts with FNIP1 and FNIP2 (Baba 2006); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25525159, 21937013, 27356891, 18234728, 19802896, 15852235, 29357828)
Ambry Genetics RCV000492464 SCV000580723 pathogenic Hereditary cancer-predisposing syndrome 2018-11-05 criteria provided, single submitter clinical testing The c.1432+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 9 of the FLCN gene. This mutation (designated IVS12+1G>A) has been identified in an individual with a personal medical history of lung cysts, pneumothorax, and skin findings characteristic of Birt-Hogg-Dube syndrome (Toro JR et al. J. Med. Genet. 2008 Jun;45:321-31). 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.
Invitae RCV000239711 SCV000632843 likely pathogenic Multiple fibrofolliculomas 2020-09-19 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 12 of the FLCN gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in an individual affected with Birt-Hogg-Dubé syndrome (PMID: 18234728) and an individual affected with familial colorectal cancer (PMID: 27356891). This variant is also known as IVS12+1G>A. ClinVar contains an entry for this variant (Variation ID: 253252). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in FLCN are known to be pathogenic (PMID: 15852235). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000813 SCV001157878 pathogenic not specified 2018-10-08 criteria provided, single submitter clinical testing The FLCN c.1432+1G>A variant (rs755959303), also known as IVS12+1G>A, is reported in the literature in an individual with Birt-Hogg-Dube syndrome (Toro 2008) and an individual with colorectal cancer (Dobbins 2016). This variant is classified as likely pathogenic or pathogenic in ClinVar (Variation ID: 253252). It is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant abolishes the canonical splice donor site of intron 12, which is likely to disrupt gene function. Based on available information, this variant is considered to be pathogenic. REFERENCES Dobbins SE et al. Undefined familial colorectal cancer and the role of pleiotropism in cancer susceptibility genes. Fam Cancer. 2016 Oct;15(4):593-9. Toro JR et al. BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dube syndrome: a new series of 50 families and a review of published reports. J Med Genet. 2008 Jun;45(6):321-31.

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