Table 3.
Classification of germline DICER1 Platform variants based on Variant Curation Expert Panel (VCEP) criteria. Classification of germline DICER1 Platform variants based on Variant Curation Expert Panel (VCEP) criteria based on functional and clinical data provided in this study and previous reports. cERMS: cervical embryonal rhabdomyosarcoma, MNG: multinodular goiter
| DICER1 variant | ||||
|---|---|---|---|---|
| VCEP Criteria | c.2407G>A, p.G803R (Original reference: (Palculict et al., 2016) with additional information from this study) | c.2414T>C, p.L805P (Diets et al., 2018) | c.2516C>T, p.S839F (Rio Frio et al., 2011) (de Kock et al., 2014) | c.2642T>C, p.L881P (van Engelen et al., 2018) |
| PM2 Supporting: Allele frequency < 0.000005 across gnomAD with no more than one allele in any subpopulation and at least 20 x coverage. | PM2_Supporting: variant absent from gnomAD. | PM2_Supporting: Variant absent from gnomAD. | PM2_Supporting: Variant absent from gnomAD. | PM2_Supporting: Variant absent from gnomAD. |
| PP1 Supporting: 3–4 meioses across ≥ 1 family. Moderate: 5–6 meioses across ≥ 1 family. | PP1 not applied: 1 meiosis across 1 family. | PP1 not applied: No segregation data. | PP1_Moderate: 19 meioses across 1 family. | PP1_Supporting: 3 meioses across 1 family. |
| PP3 Supporting: For missense variants, REVEL score ≥ 0.75. | PP3_Supporting: REVEL score: 0.807. | PP3_Supporting: REVEL score: 0.944. | PP3 not applied: REVEL score: 0.519. | PP3_Supporting: REVEL score: 0.906. |
| PP4 Supporting: Somatic tumor testing identifies somatic hotspot second hit and no additional somatic LOF variants | PP4_Supporting: DICER1 c.5428G>C, p.D1810H in MNG. | PP4_Supporting: DICER1 c.5439G>T, p.E1813D in cERMS. | PP4_Supporting: DICER1 c.5428G>T, p.D1810Y and DICER1 c.5439G>T, p.E1813D in MNG. | PP4_Supporting: DICER1 c.5125G>A, p.D1709N in cystic nephroma. |
| PS3 Supporting: In vitro cleavage assay shows failure or severly reduced capacity to produce either 5p or 3p miRNAs from a pre-mIRNA | PS3_ Supporting: No cleavage. | PS3_Supporting: No cleavage. | PS3_Supporting: Impaired cleavage. | PS3_Supporting: Impaired cleavage. |
| PS4 Supporting: 1–1.5 phenotype points. Unrelated probands may contribute up to 1 point each. | PS4_Supporting: 1 phenotype point: Wilms tumor and MNG. | PS4_Supporting: 1 phenotype point: cERMS. | PS4_Supporting: 1 phenotype point: MNG. | PS4_Supporting: 1 phenotype point: Cystic nephroma, MNG, cystic lung lesion, pineal cyst. |
| Total points on modified Bayesian point system (variant classification) | 5 (5 supporting criteria): Variant of uncertain significance. | 5 (5 supporting criteria): Variant of uncertain significance. | 6 (4 supporting and 1 moderate criteria): Likely pathogenic. | 6 (6 supporting criteria): Likely pathogenic. |