Submissions for variant NM_144997.7(FLCN):c.1084C>T (p.Arg362Cys)

gnomAD frequency: 0.00002  dbSNP: rs557336321

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000564803	SCV000673422	benign	Hereditary cancer-predisposing syndrome	2024-02-23	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000691604	SCV000819390	uncertain significance	Birt-Hogg-Dube syndrome	2024-12-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 362 of the FLCN protein (p.Arg362Cys). This variant is present in population databases (rs557336321, gnomAD 0.003%). This missense change has been observed in individual(s) with renal cell carcinoma (PMID: 35441217). ClinVar contains an entry for this variant (Variation ID: 485585). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt FLCN protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects FLCN function (PMID: 21538689, 33137092). 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.
Illumina Laboratory Services, Illumina	RCV001127833	SCV001287182	uncertain significance	Familial spontaneous pneumothorax	2017-04-28	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV000691604	SCV001287183	uncertain significance	Birt-Hogg-Dube syndrome	2017-04-28	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Baylor Genetics	RCV000691604	SCV002030098	uncertain significance	Birt-Hogg-Dube syndrome	2021-05-25	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Fulgent Genetics, Fulgent Genetics	RCV005004253	SCV002783063	uncertain significance	Familial spontaneous pneumothorax; Nonpapillary renal cell carcinoma; Colorectal cancer; Birt-Hogg-Dube syndrome 1	2024-03-27	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003321681	SCV004026705	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003409849	SCV004116445	uncertain significance	FLCN-related disorder	2023-01-26	criteria provided, single submitter	clinical testing	The FLCN c.1084C>T variant is predicted to result in the amino acid substitution p.Arg362Cys. This variant has been reported in an individual with breast cancer (Chen et al. 2020. PubMed ID: 32091409). In silico structural analyese and experimental studies using a yeast based assay suggest this variant may impact protein function (Clausen et al. 2020. PubMed ID: 33137092). This variant is reported in 0.0027% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-17120475-G-A) and is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/485585/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV000691604	SCV004195329	uncertain significance	Birt-Hogg-Dube syndrome	2023-08-23	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003478283	SCV004218907	uncertain significance	not provided	2024-11-08	criteria provided, single submitter	clinical testing	The FLCN c.1084C>T (p.Arg362Cys) variant has been reported in the published literature in an individual with renal cell carcinoma (PMID: 35441217 (2022)). Functional studies demonstrated that this variant was damaging to protein function (PMID: 33137092 (2020), 21538689 (2011)). The frequency of this variant in the general population, 0.000027 (3/113102 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
GeneDx	RCV003478283	SCV005078799	uncertain significance	not provided	2024-01-21	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with clear cell renal carcinoma in published literature (PMID: 35441217); Published functional studies suggest a damaging impact on protein levels and stability (PMID: 33137092); This variant is associated with the following publications: (PMID: 21538689, 24755471, 17028174, 35441217, 33137092, 32091409)