Table 1.
List of germline DICER1 missense variants in persons with DICER1 tumor predisposition syndrome (DTPS). List of missense variants in the DICER1 gene identified in germline DNA of patients with phenotypes associated with DICER1 tumor predisposition syndrome (DTPS) compiled using data reported by (de Kock et al., 2019). Variants functionally investigated in this study are in bold. Variants that had a population allele frequency under 0.01% and predicted to be pathogenic by 2/3 in silico predictors are underlined to show clustering of possibly pathogenic variants in platform domain. iSecond hit in euthyroid multinodular goiters of persons bearing the germline p.S839F variant was described in (31). iiSecond hit in differentiated thyroid carcinomas and multinodular goiter bearing the germline p.S1814L variant was described in (32). ^ Classified by the DICER1 Variant Curation Expert Panel (VCEP).# Likely Pathogenic based on our laboratory results (ClinVar entries: 933014, 690445). B: benign, CN: cystic nephroma, DTC: differentiated thyroid carcinoma, DTPS: DICER1 tumor predisposition syndrome, FH: favorable histology, LB: likely benign, LP: likely pathogenic, MNG: multinodular goiter, NOS: not otherwise specified, P: pathogenic, PPB: pleuropulmonary blastoma, PTC: papillary thyroid carcinoma, SLCT: Sertoli-Leydig cell tumor, VUS: variant of unknown significance, WES: whole exome sequencing, WGS: Whole genome sequencing, WT: Wilms tumor
| # | Reference | Phenotypes | Protein change | cDNA change | Domain | Second somatic pathogenic variant found in tumor | Lesion with second hit | ClinVar classification | gnomAD allele frequency (%) | PolyPhen2 Prediction | Sift Prediction | Missense 3D Prediction |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | Zhang J, 2015 PMID: 26580448 | Rhabdo-myosarcoma | p.V62I | c.184G>A | DExD/H-box helicase | Not done | Not done | LB/VUS | 7.96E-04 | Benign | Tolerated | Neutral |
| 2 | Walz AL, 2015 PMID: 25670082 | WT-FH | p.I85M | c.255C>G | DExD/H-box helicase | Not found via WES and SNP array | None | LB | 1.71E-02 | Benign | Tolerated | Neutral |
| 3 | Gadd S, 2017 PMID: 28825729 | WT-FH | p.G162D | c.485G>A | DExD/H-box helicase | Not found via WES and SNP array | None | B/LB | 7.26E-02 | Benign | Tolerated | Damaging: disallowed phi/psi |
| 4 | Wasserman JD, 2018 PMID: 29474644 | PTC | p.P375R | c.1124C>G | DExD/H-box helicase | c.5428G > T, p.D1810Y | PTC | B/LB/VUS | 3.29E-02 | Probably damaging | Not tolerated | Neutral |
| 5 | Brenneman M, 2015 PMID: 26925222 | PPB | p.I582T | c.1745T>C | DExD/H-box helicase | Not specified whether looked for or not | None | VUS | 8.02E-04 | Probably damaging | Not tolerated | Neutral |
| 6 | Palculict TB, 2016 PMID: 26566882 | WT-NOS, MNG | p.G803R | c.2407G>A | Platform | Loss of heterozygosity | WT | LP# | Not present | Probably damaging | Not tolerated | Damaging: Clash, buried glycine change, buried charge introduction |
| 7 | Diets IJ, 2018 PMID: 29351919 | cERMS | p.L805P | c.2414T>C | Platform | c.5439G > T, p.E1813D | cERMS | LP# | Not present | Probably damaging | Not tolerated | Damaging: Proline introduced, disallowed phi/psi, buried/ exposed introduction |
| 8 | Rio Frio T, 2011 PMID: 21205968 | MNG | p.S839F | c.2516C>T | Platform | c.5428G > T, p.D1810Yi; c.5439G > T, p.E1813Di | MNG | VUS/LP/P | Not present | Possibly damaging | Not tolerated | Neutral |
| 9 | Wu MK, 2013 PMID: 23620094 | WT-NOS | p.A872T | c.2614G>A | Platform | Not found via Sanger sequencing | None | B^ | 8.11E-02 | Probably damaging | Tolerated | Neutral |
| 10 | Van Engelen K, 2017 PMID: 28960912 | Cystic nephroma, pineal cyst, cystic lung lesion, MNG | p.L881P | c.2642T>C | Platform | Not done | Not done | LP^# | Not present | Probably damaging | Not tolerated | Damaging: Buried proline introduced, disallowed phi/psi |
| 11 | Walz AL, 2015 PMID: 25670082 | WT-FH | p.R1368C | c.4102C>T | RNase IIIa | Not found via WES and SNP array | None | VUS, LB | 3.54E-03 | Possibly damaging | Tolerated | Neutral |
| 12 | Hill DA, 2009 PMID: 19556464 | PPB | p.L1583R | c.4748T>G | RNase IIIa | Not done | Not done | LP^ | N/P | Probably damaging | Not tolerated | Damaging: Buried hydrophilic introduced, buried charge introduced |
| 13 | Zhang J, 2015 PMID: 26580448 | Rhabdo-myosarcoma | p.R1630C | c.4888C>T | Between RNase IIIa and IIIb | Not done | Not done | VUS/LB | 1.77E-03 | Benign | Tolerated | N/A |
| 14 | Brenneman M, 2015 PMID: 26925222 | PPB | p.G1708E | c.5123G>A | RNase IIIb | c.5438A > G, p.E1813G | PPB | LP/P | Not present | Probably damaging | Not tolerated | Damaging: Buried charge introduced, buried glycine replaced |
| 15 | Wu MK, 2013 PMID: 23620094 | WT-NOS | p.L1777H | c.5330T>A | RNase IIIb | Not found via Sanger sequencing | None | LB/VUS | 2.93E-05 | Probably damaging | Tolerated | Neutral |
| 16 | Wu MK, 2016 PMID: 26545620 | DTC, SLCT, MNG, CN | p.S1814L | c.5441C>T | RNase IIIb | c.5126A > G, p.D1709Gii; c.5425G > A, p.G1809Rii; c.5428G > C, p.D1810Hii | DTC, MNG, SLCT | P^ | Not present | Probably damaging | Not tolerated | Damaging: Buried H-bond breakage |
| 17 | Brenneman M, 2015 PMID: 26925222 | PPB | p.D1822V | c.5465A>T | RNase IIIb | Not specified whether looked for or not | None | LP^ | N/P | Probably damaging | Not tolerated | Neutral |
| 18 | Wegert J, 2015 PMID: 25670083 | WT-NOS | p.G1886R | c.5656G>A | dsRBD | Not found via WGS | None | VUS^ | N/P | Probably damaging | Tolerated | Neutral |