Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001026310 | SCV001188665 | likely benign | Hereditary cancer-predisposing syndrome | 2023-03-27 | criteria provided, single submitter | clinical testing | This alteration is classified as likely 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 |
RCV001247341 | SCV001420755 | uncertain significance | Birt-Hogg-Dube syndrome | 2024-12-05 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 245 of the FLCN protein (p.Thr245Lys). This variant is present in population databases (rs371401039, gnomAD 0.002%). 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: 826983). 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 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. |
| St. |
RCV001247341 | SCV001737473 | uncertain significance | Birt-Hogg-Dube syndrome | 2021-05-20 | criteria provided, single submitter | clinical testing | The FLCN c.734C>A (p.Thr245Lys) missense change has a maximum frequency of 0.0015% in gnomAD v2.1.1 (PM2_supporting; https://gnomad.broadinstitute.org/variant/17-17125860-G-T?dataset=gnomad_r2_1). Seven of seven in silico tools predict a deleterious effect of this variant on protein function (PP3), but to our knowledge these predictions have not been confirmed by functional assays. To our knowledge, this variant has not been reported in individuals with Birt-Hogg-Dubé syndrome. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_supporting, PP3. |
| Gene |
RCV001759715 | SCV002005421 | uncertain significance | not provided | 2022-02-14 | criteria provided, single submitter | clinical testing | Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge |
| Fulgent Genetics, |
RCV005004488 | SCV002778340 | uncertain significance | Familial spontaneous pneumothorax; Nonpapillary renal cell carcinoma; Colorectal cancer; Birt-Hogg-Dube syndrome 1 | 2024-05-17 | criteria provided, single submitter | clinical testing | |
| Baylor Genetics | RCV004570066 | SCV005058696 | uncertain significance | Birt-Hogg-Dube syndrome 1 | 2024-01-01 | criteria provided, single submitter | clinical testing |