ClinVar Genomic variation as it relates to human health

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28202063)

Variant summary: FLCN c.1387T>C (p.Tyr463His) results in a conservative amino acid change located in the Folliculin, DENN domain (IPR032035) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 251424 control chromosomes (gnomAD). The observed variant frequency is approximately 35 fold of the estimated maximal expected allele frequency for a pathogenic variant in FLCN causing Birt-Hogg-Dube Syndrome phenotype (1.3e-06), strongly suggesting that the variant is benign. c.1387T>C has been reported in the literature in an individual affected with breast cancer (example: Jalkh_2017). One study have provided experimental evidence that this variant does not alter mRNA splicing (example: Liu_2019). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS and likely benign. Based on the evidence outlined above, the variant was classified as likely benign.

In the published literature, the variant has been reported in individuals with breast cancer (PMID: 28202063 (2017)) and acute lymphoblastic leukemia (ALL) (PMID: 26580448 (2015)). The frequency of this variant in the general population, 0.0002 (7/35438 chromosomes in Latino/Admixed American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.

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.

The FLCN p.Tyr463His variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs770077517) and ClinVar (classified as a VUS by Invitae and Ambry Genetics). The variant was also identified in control databases in 13 of 282816 chromosomes at a frequency of 0.00004597 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Latino in 7 of 35438 chromosomes (freq: 0.000198) and European (non-Finnish) in 6 of 129160 chromosomes (freq: 0.000046), but was not observed in the African, Ashkenazi Jewish, East Asian, European (Finnish), Other or South Asian populations. The p.Tyr463 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and four of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

The FLCN c.1387T>C variant is predicted to result in the amino acid substitution p.Tyr463His. This variant was reported in individuals with Breast cancer (Table 2 in Jalkh et al 2017. PubMed ID: 28202063; Bhai P et al 2021. PubMed ID: 34326862). This variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD and is classified as benign or uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/409380/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.