ClinVar Miner

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

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CSER _CC_NCGL, University of Washington RCV000148504 SCV000190215 uncertain significance Multiple fibrofolliculomas 2015-12-01 criteria provided, single submitter research
Ambry Genetics RCV000163388 SCV000213928 likely benign Hereditary cancer-predisposing syndrome 2019-05-03 criteria provided, single submitter clinical testing 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
Invitae RCV000148504 SCV000291452 likely benign Multiple fibrofolliculomas 2019-12-16 criteria provided, single submitter clinical testing
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
Illumina Clinical Services Laboratory,Illumina RCV000148504 SCV000401012 likely benign Multiple fibrofolliculomas 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
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.
Mendelics RCV000148504 SCV001140313 uncertain significance Multiple fibrofolliculomas 2019-05-28 criteria provided, single submitter clinical testing
ITMI RCV000121104 SCV000085272 not provided not specified 2013-09-19 no assertion provided reference population

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