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NM_144997.7(FLCN):c.715C>T (p.Arg239Cys)

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Interpretation:
Conflicting interpretations of pathogenicity​

Likely benign(4);Uncertain significance(4)

Review status:
criteria provided, conflicting interpretations
Submissions:
9 (Most recent: Nov 4, 2021)
Last evaluated:
Nov 3, 2021
Accession:
VCV000134427.11
Variation ID:
134427
Description:
single nucleotide variant
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NM_144997.7(FLCN):c.715C>T (p.Arg239Cys)

Allele ID
138166
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
17p11.2
Genomic location
17: 17222565 (GRCh38) GRCh38 UCSC
17: 17125879 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
Q8NFG4:p.Arg239Cys
LRG_325t1:c.715C>T
LRG_325:g.19624C>T
... more HGVS
Protein change
R239C, R257C
Other names
-
Canonical SPDI
NC_000017.11:17222564:G:A
Functional consequence
-
Global minor allele frequency (GMAF)
0.00060 (A)

Allele frequency
The Genome Aggregation Database (gnomAD) 0.00024
Trans-Omics for Precision Medicine (TOPMed) 0.00025
The Genome Aggregation Database (gnomAD) 0.00029
Trans-Omics for Precision Medicine (TOPMed) 0.00023
1000 Genomes Project 0.00060
Exome Aggregation Consortium (ExAC) 0.00025
The Genome Aggregation Database (gnomAD), exomes 0.00026
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00046
Links
ClinGen: CA159776
UniProtKB: Q8NFG4#VAR_066026
dbSNP: rs78683075
VarSome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Likely benign 1 criteria provided, single submitter May 3, 2019 RCV000163388.4
Likely benign 1 criteria provided, single submitter May 13, 2021 RCV000656850.2
Uncertain significance 1 criteria provided, single submitter Nov 3, 2021 RCV001762262.1
Conflicting interpretations of pathogenicity 5 criteria provided, conflicting interpretations Dec 3, 2020 RCV000148504.14
not provided 1 no assertion provided Sep 19, 2013 RCV000121104.2
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
FLCN Sufficient evidence for dosage pathogenicity No evidence available GRCh38
GRCh37
1159 1275

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Uncertain significance
(Jul 18, 2016)
criteria provided, single submitter
()
Method: clinical testing
Birt-Hogg-Dube Syndrome
Allele origin: germline
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia
Accession: SCV000298054.1
Submitted: (Aug 10, 2016)
Comment:
Clinical Testing
Evidence details
Uncertain significance
(Dec 01, 2015)
criteria provided, single submitter
Method: research
Multiple fibrofolliculomas
(Autosomal dominant inheritance)
Allele origin: germline
CSER _CC_NCGL, University of Washington
Study: ESP 6500 variant annotation
Accession: SCV000190215.2
Submitted: (Feb 29, 2016)
Comments (2):
Found in patient having exome sequencing for personal and/or family history of colon cancer and/or polyps. Patient has 20 colon polyps by age 50 and … (more)
Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript
Evidence details
Likely benign
(Apr 27, 2017)
criteria provided, single submitter
Method: clinical testing
Multiple fibrofolliculomas
Allele origin: germline
Illumina Clinical Services Laboratory,Illumina
Accession: SCV000401012.3
Submitted: (Feb 20, 2020)
Evidence details
Publications
PubMed (1)
Comment:
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, … (more)
Likely benign
(May 03, 2019)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Ambry Genetics
Accession: SCV000213928.5
Submitted: (Nov 30, 2020)
Evidence details
Publications
PubMed (6)
Comment:
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
Likely benign
(Dec 03, 2020)
criteria provided, single submitter
Method: clinical testing
Multiple fibrofolliculomas
Allele origin: germline
Invitae
Accession: SCV000291452.8
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (1)
Uncertain significance
(May 28, 2019)
criteria provided, single submitter
Method: clinical testing
Multiple fibrofolliculomas
Allele origin: unknown
Mendelics
Accession: SCV001140313.1
Submitted: (Oct 22, 2019)
Evidence details
Likely benign
(May 13, 2021)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV000616724.3
Submitted: (Sep 28, 2021)
Evidence details
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with FLCN-related tumors and other cancers (Woodward … (more)
Uncertain significance
(Nov 03, 2021)
criteria provided, single submitter
Method: clinical testing
Colorectal cancer
Allele origin: germline
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002009831.1
Submitted: (Nov 04, 2021)
Evidence details
not provided
(Sep 19, 2013)
no assertion provided
Method: reference population
AllHighlyPenetrant
Allele origin: germline
ITMI
Accession: SCV000085272.1
Submitted: (May 29, 2014)
Comment:
Please see associated publication for description of ethnicities
Evidence details
Publications
PubMed (1)

Functional evidence

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There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Citations for this variant

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Title Author Journal Year Link
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Nykamp K Genetics in medicine : official journal of the American College of Medical Genetics 2017 PMID: 28492532
Multilocus Inherited Neoplasia Alleles Syndrome: A Case Series and Review. Whitworth J JAMA oncology 2016 PMID: 26659639
Actionable exomic incidental findings in 6503 participants: challenges of variant classification. Amendola LM Genome research 2015 PMID: 25637381
Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing. Bodian DL PloS one 2014 PMID: 24728327
Deleterious- and disease-allele prevalence in healthy individuals: insights from current predictions, mutation databases, and population-scale resequencing. Xue Y American journal of human genetics 2012 PMID: 23217326
Gene expression and protein array studies of folliculin-regulated pathways. Reiman A Anticancer research 2012 PMID: 23155228
Birt Hogg-Dubé syndrome-associated FLCN mutations disrupt protein stability. Nahorski MS Human mutation 2011 PMID: 21538689
Familial non-VHL clear cell (conventional) renal cell carcinoma: clinical features, segregation analysis, and mutation analysis of FLCN. Woodward ER Clinical cancer research : an official journal of the American Association for Cancer Research 2008 PMID: 18794106

Text-mined citations for rs78683075...

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These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 27, 2021