ClinVar Miner

Submissions for variant NM_144997.7(FLCN):c.715C>T (p.Arg239Cys) (rs78683075)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000163388 SCV000213928 likely benign Hereditary cancer-predisposing syndrome 2018-04-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Co-occurence with a mutation in another gene that clearly explains a proband's phenotype,Other data supporting benign classification,Subpopulation frequency in support of benign classification
CSER_CC_NCGL; University of Washington Medical Center RCV000148504 SCV000190215 uncertain significance Multiple fibrofolliculomas 2015-12-01 criteria provided, single submitter research
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000148504 SCV000298054 uncertain significance Multiple fibrofolliculomas 2016-07-18 criteria provided, single submitter clinical testing
GeneDx RCV000656850 SCV000616724 uncertain significance not provided 2018-10-02 criteria provided, single submitter clinical testing This variant is denoted FLCN c.715C>T at the cDNA level, p.Arg239Cys (R239C) at the protein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). This variant, previously published as c.1213C>T using alternate numbering, was observed in an individual with bilateral clear cell renal carcinoma (Woodward 2008), and an individual with chromophobe renal cancer and facial fibrofolliculomas, as well as rectal cancer and gastroesophageal junction cancer, who was found to also carry a TP53 variant of uncertain significance (Whitworth 2016). This variant has also been identified in at least one individual with breast cancer, and in healthy controls (Bodian 2014, Melloni 2017). In vitro analysis of FLCN Arg239Cys showed decreased protein stability compared to wild-type (Nahorski 2011). FLCN Arg239Cys was observed at an allele frequency of 0.05% (63/126,680) in individuals of non-Finnish European ancestry in large population cohorts (Lek 2016). FLCN Arg239Cys is not located in a known functional domain. In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether FLCN Arg239Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
ITMI RCV000121104 SCV000085272 not provided not specified 2013-09-19 no assertion provided reference population
Illumina Clinical Services Laboratory,Illumina RCV000148504 SCV000401012 likely benign Multiple fibrofolliculomas 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000148504 SCV000291452 uncertain significance Multiple fibrofolliculomas 2018-12-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 239 of the FLCN protein (p.Arg239Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs78683075, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in individuals affected with renal cell carcinoma (PMID: 18794106, 26659639). This variant is also known as c.1213C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 134427). An experimental study has shown that this missense change decreases FLCN protein stability in vitro (PMID: 21538689). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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