Table 3.
Frequencies of null variants in the cancer genes in UM cohort and controls from public database
| Gene | gnomAD Loss-of-Function Intolerance Metric (90% CI)* | UM Cohort** | gnomAD Control Cohort*** | Odds Ratio (95% CI)**** | P-value**** |
|---|---|---|---|---|---|
| # Pathogenic Variant Carriers/# Individuals (%) | |||||
| BAP1 | 0.12 (0.06 – 0.28) | 7/172 (4.1%) | 2/59095 (0.0034%) | 1255, 95% CI: 277 – 8192 | <2.2e-16 |
| BRCA1 | 0.73 (0.59 – 0.92) | 1/156 (0.64%) | 153/59095 (0.26%) | 2.5 (0.1 – 12.6) | 0.40 |
| PALB2 | 0.76 (0.58 – 1.01) | 2/156 (1.3%) | 86/59095 (0.15%) | 8.9 (1.5 – 30.6) | 0.02 |
| MLH1 | 0.37 (0.25 – 0.57) | 1/156 (0.64%) | 15/59095 (0.025%) | 25.4 (1.2 – 143.2) | 0.04 |
| MSH6 | 0.34 (0.23 – 0.50) | 1/156 (0.64%) | 65/59095 (0.11%) | 5.9 (0.3 – 30.1) | 0.17 |
| CHEK2 | 1.15 (0.87 – 1.53) | 2/156 (1.3%) | 409/59095 (0.69%) | 1.9 (0.3 – 6.3) | 0.39 |
| CTNNA1 | 0.17 (0.10 – 0.31) | 1/156 (0.64%) | 17/59095 (0.029%) | 22.4 (1.1 – 124.8) | 0.05 |
| ATM | 0.60 (0.51 – 0.71) | 1/156 (0.64%) | 198/59095 (0.34%) | 1.9 (0.1 – 9.7) | 0.51 |
| RECQL4 | 0.96 (0.77 – 1.21) | 1/29 (3.4%) | 232/59095 (0.39%) | 9.1 (0.4 – 48.2) | 0.11 |
| SMARCE1 | 0.04 (0.01 – 0.19) | 1/29 (3.4%) | 1/59095 (0.0017%) | 2047 (52 – 4.5e15) | 0.001 |
| TP53AIP1 | 1.73 (0.82 – 1.95) | 1/29 (3.4%) | 987/59095 (1.7%) | 2.1 (0.1 – 11.1) | 0.47 |
| DLEC1 | 0.74 (0.61 – 0.91) | 1/29 (3.4%) | 844/59095 (1.4%) | 2.4 (0.1 – 13.0) | 0.41 |
| MMS19 | 0.27 (0.18 – 0.42) | 1/29 (3.4%) | 33/59095 (0.056%) | 63.8 (3.0 – 354.2) | 0.02 |
| POLI | 0.61 (0.41 – 0.93) | 1/29 (3.4%) | 60/59095 (0.10%) | 35.1 (1.7 – 191.2) | 0.03 |
This metric is the ratio of the observed number of loss-of-function variants in the gene in gnomAD to what would be expected if such variants were selectively neutral. Values closer to zero indicate loss-of-function intolerance (fewer than expected). Obtained from gnomAD v2.1.1 at https://gnomad.broadinstitute.org on June 28, 2019.
One UM patient with large germline deletion of BAP1 was not counted in order to make a valid comparison with gnomAD.
The gnomAD non-Finnish European non-cancer cohort comprised 59,095 unrelated individuals with data (51,377 with exomes and 7,718 with whole genomes). The number of carriers of pathogenic variants meeting the same criteria used in the UM cohort was estimated for each gene by the number of variant alleles at missense variants reported as pathogenic or likely pathogenic in ClinVar and null (stop, large deletion, frameshift, canonical splicing) variants not reported as benign and/or variants of uncertain significance in ClinVar. This approximation assumes that multiple pathogenic variant alleles do not appear on the same haplotype and that there are no individuals who are compound heterozygotes or homozygotes for pathogenic variants. To the extent that these assumptions are not met, the frequency of carriers in the control cohort would be overestimated, which would bias associations toward the null. No pathogenic or likely pathogenic missense variants were reported in ClinVar for for DLEC1, MMS19, POLI, and TP53AIP1.
Carrying pathogenic variants in genes highlighted in bold was associated with higher odds of UM (P ≤ 0.05).