Table 1. Novel and rare (population MAF < 1%) germline UNC5C variants identified in 529 CRC and/or polyposis families.
| aVariant [protein domain] | Population MAF% (1000G/ESP/ExAC) | Protein function prediction (score) | bEvolutionary conservation (PhyloP /PhastCons) | cSplice-site prediction | Proband’s phenotype | Familial cancer history (Fig. 1) | Criteria | Co-segregation analysis | CRC cases vs. controls (MCC-Spain) | CRC cases vs. controls (Coissieux et al.)25 |
|---|---|---|---|---|---|---|---|---|---|---|
| c.932C > T (p.T311M) [Thrombospondin] | rs200437262 (-/0.04/0.012) | dPPH2: PrD (0.983)/PsD (0.765) SIFT: D (0.02) Mut. taster: D Condel: D (0.531) | 5.987/0.976 | Creates ESS and disrupts ESE RNA study: no change | CRC (54), 40-50 polyps | Fam A: CRC (79) and SC (83), BC (67), H&N ca. (79), PC (79), CLL (75) | Attenuated polyposis | Non-carriers: Father (CRC 79, and SC 83), daughter (unaffected, 29) | 2/1334 vs. 1/2740 (p = 0.251) | n.a. |
| c.1057G > A (p.D353N) [Thrombospondin] | rs145155041 (0.14/0.15/0.15) | PPH2: PsD (0.613)/N (0.166) SIFT: N (0.15) Mut. Taster: D Condel: N (0.492) | 3.145/0.954 | Disrupts ESE | Tubular adenoma with low-grade dysplasia (43) | Fam B: CRC (71), CRC (68), CRC (70), SC (56), PC (69) | Bethesda | Non-carriers: Father (CRC, 71) | 12/1334 vs. 24/2742 (p = 1) | 5/755 vs. 16/2740 (p = 0.791) |
| c.1235A > C (p.D412A) [Cytoplasmic domain] | -(-/-/0.002) | PPH2: PrD (0.999/0.994) SIFT: N (0.09) Mut. Taster: D Condel: D (0.611) | 5.127/1 | Disrupts ESE | CRC (59) | Fam C: CRC (52), CRC (39) | Amsterdam | Non-carrier: Daughter (CRC, 39) | n.a. | n.a. |
| c.1807C > T (p.R603C) [ZU5] | rs139568380 (0.04/0.15/0.093) | PPH2: PrD (1/0.975) SIFT: D (0) Mut. Taster: D Condel: N (0.467) | 1.628/1 | No change | CRC (33), 33-39 polyps | Fam D: Brain ca. (68), TC (40) | Attenuated polyposis | n.a. | n.a. | 2/1801 vs. 9/4044 (p = 0.521) |
| c.1882_1883delinsAA (p.A628K) [ZU5] | - | PPH2: N (0.042/0.042) SIFT: N (0.87) Mut. Taster: D Condel: n.a. | 1.733/0.24 −0.359/0.217 | No change | 15 polyps (42) | Fam E: Gallbladder ca. (63) | Attenuated polyposis (<20 polyps) | n.a. | n.a. | 5/1801 vs. 5/4144 (p = 0.182); e4/1023 vs. 2/1121 (p = 0.434); TOTAL: 9/2824vs. 7/5265(p = 0.111) |
| c.2002G > A (p.A668T) [Cytoplasmic domain] | rs187196396 (0.02/ -/0.005) | PPH2: PsD (0.813)/N (0.083) SIFT: N (0.64) Mut. Taster: D Condel: D (0.536) | 1.304/0.999 | No change | CRC (49), 50 polyps | Fam F: CRC (78) | Attenuated polyposis | n.a. | 2/1336 vs.2/2743 (p = 0.601) | n.a. |
| c.2210G > A (p.S737N) [Cytoplasmic domain] | - | PPH2: PrD (0.981)/PsD (0.843) SIFT: N (0.64) Mut. Taster: D Condel: N (0.461) | 3.545/1 | No change | CRC (71) | Fam G: CRC (55), CRC (69), CRC (64) | Bethesda | Carrier: Son (villous adenoma with high-grade dysplasia, 41) | n.a. | n.a. |
| c.2240A > G (p.D747G) [Cytoplasmic domain] | rs146792764 (0.04/0.007/0.015) | PPH2: PrD (0.983/0.982) SIFT: D (0.04) Mut. Taster: D Condel: D (0.582) | 3.492/0.995 | Creates donor site and disrupts ESE | 4 polyps (39) | Fam H: CRC (62), PC (69) | No criteria | n.a. | 3/1336 vs.5/2744 (p = 0.722) | n.a. |
Characteristics of the variants and carrier families, and results of association studies in CRC patients and controls.
bPhyloP score (values between −14 and +6): Sites predicted to be conserved are assigned positive scores. PhastCons score (values between 0–1): It reflects the probability that each nucleotide belongs to a conserved element, based on the multiple alignment of genome sequences of 46 different species (the closer the value is to 1, the more probable the nucleotide is conserved).
cPrediction obtained from the Human Splicing Finder (http://http://www.umd.be/).
dPolyphen-2: HumDiv/HumVar scores.
eKüry et al. (2014)26.