Submissions for variant NM_144997.7(FLCN):c.802C>T (p.Arg268Trp)

gnomAD frequency: 0.00007  dbSNP: rs762370059

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000819183	SCV000959829	uncertain significance	Birt-Hogg-Dube syndrome	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 268 of the FLCN protein (p.Arg268Trp). This variant is present in population databases (rs762370059, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with FLCN-related conditions. ClinVar contains an entry for this variant (Variation ID: 661706). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FLCN protein function with a positive predictive value of 80%. 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.
Ambry Genetics	RCV001027085	SCV001189587	benign	Hereditary cancer-predisposing syndrome	2023-05-26	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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.
GeneDx	RCV001824384	SCV002073974	uncertain significance	not provided	2023-11-06	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28481359, 31360874, 28873162)
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002268311	SCV002551350	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002507435	SCV002815074	uncertain significance	Birt-Hogg-Dube syndrome; Familial spontaneous pneumothorax; Potocki-Lupski syndrome; Nonpapillary renal cell carcinoma; Colorectal cancer	2022-05-10	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003892754	SCV004709635	uncertain significance	FLCN-related condition	2023-12-05	criteria provided, single submitter	clinical testing	The FLCN c.802C>T variant is predicted to result in the amino acid substitution p.Arg268Trp. This variant was reported as a variant of uncertain significance in a colorectal cancer cohort (supplemental data, Toh et al. 2018. PubMed ID: 31360874). This variant is reported in 0.029% of alleles in individuals of South Asian descent in gnomAD and has conflicting interpretations of pathogenicity in ClinVar ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/661706). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.