Table 2.
Candidate genes to the germline predisposition to serrated polyposis syndrome after final prioritization based on germline only and germline-somatic paired analysis. Candidate genes to the germline predisposition to SPS after final prioritization based on germline only and germline-somatic paired analysis.
| Gene | Family | Variant | Pred. Tools | gnomAD | Protein Domain Location | Biological Process | Analysis Approach | Selection Criteria |
|---|---|---|---|---|---|---|---|---|
| ANXA10 | SPS.12 | c.692A>G p.(Asp231Gly) | 6 | 0.000036 | Annexin 3 (171–243 AA) | growth regulation; apoptosis; cell division |
G | Histological marker for serrated pathway |
| ASXL1 | SPS.13 | c.2110G>A p.(Gly704Arg) | 6 | 0.000668 | No | transcription; cell morphogenesis; hemopoiesis; homeostasis of number of cells; protein deubiquitination; |
G | Involvement in cancer development |
| CFTR | SPS.3 | c.3995C>A p.(Pro1332His) | 6 | N/A | Nucleotide -Binding 2 (1207–1436 AA) |
transmembrane transport; positive regulation of voltage-gated chloride channel activity; protein deubiquitination; | G | Involvement in cancer development |
| SPS.14 | c.1601C>A p.(Ala534Glu) | 3 | 0.0000159 | Nucleotide -Binding 1 (390–645 AA) |
||||
| DOT1L | SPS.11 | c.3307G>A p.(Val1103Met) | 5 | 0.0000349 | No | chromatin silencing; histone H3-K79 methylation; regulation of JAK-STAT cascade; telomere organization; DNA repair |
G | Senescence and epigenetics regulator candidate |
| HIC1 | SPS.14 | c.1295A>G p.(Gln432Arg) | 3 | N/A | Zinc finger 1 (439–459 AA) | regulation of transcription; positive regulation of DNA damage response, signal transduction by p53 class mediator | G-S paired analysis | Involvement in cancer development |
| INO80 | SPS.6 | c.4271G>C p.(Arg1424Pro) | 5 | 0.00022 | No | mitotic sister chromatid segregation; double-strand break repair via homologous recombination | G | Senescence candidate |
| KLF3 | SPS.11 | c.275C>T p.(Ser92Leu) | 4 | 0.000203 | No | regulation of transcription; cellular response to peptide | G | Involvement in cancer development |
| MCM3AP | SPS.4 | c.1592A>G p.(Glu531Gly) |
4 | 0.000502 | No | mRNA transport; nucleosome organization; somatic hypermutation of immunoglobulin genes | G | Epigenetics regulator candidate |
| SPS.7 | c.5327T>C p.(Val1776Ala) |
6 | 0.000191 | No | ||||
| MCM8 | SPS.6 | c.876-1delG | N/A | N/A | No | G1/S transition of mitotic cell cycle; mitotic cell cycle; double-strand break repair via homologous | G | Involvement in cancer development |
| PDLIM2 | SPS.7 | p.(Pro130Leu) | 3 | N/A | No | stability of Nuclear Factor kappa-B (NFκB) and other transcription factors; polarized cell migration | G-S paired analysis | Involvement in cancer development |
| POLD1 | SPS.7 | c.1941delG p.(Lys648fs) | N/A | N/A | Polymerase domain (581–910 AA) |
mitotic cell cycle; DNA replication; DNA repair; DNA replication proofreading; DNA damage response | G | Involvement in cancer development |
| TP53BP1 | SPS.13 | c.3835G>A p.(Glu1279Lys) | 6 | 0.000008 | No | DNA repair; positive regulation of transcription; DNA damage checkpoint; protein sumoylation | G | Senescence candidate |
| WNK2 | SPS.4 | c.4820C>T p.(Ala1607Val) | 5 | 0.0000788 | No | protein phosphorylation; negative regulation of cell proliferation; regulation of ion homeostasis | G | Involvement in cancer development |
| SPS.6 | c.6157G>A p.(Val2053Ile) | 5 | 0.0000434 | No | ||||
| WRN | SPS.1 | c.2023G>C p.(Glu675Gln) | 4 | 0.00000795 | Helicase ATP-binding (558–724 AA) | telomere maintenance: DNA synthesis involved in DNA repair; replicative cell aging; DNA metabolic process | G | Senescence candidate |
Pred. tools: score given by the in-house pipeline based on missense pathogenicity prediction tools (0–6). gnomAD, genome aggregation database variant frequency. G, germline; S, somatic; N/A, Not Applicable or Not Available. AA, amino acid.