Table 1.
Case-control association analysis for BRCA2 missense variants affecting the DBD and PTVs in breast cancer and ovarian cancer
|
Case |
Controls |
Cancer risk |
||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| # mut | # tested | Freq (%) | # mut | # tested | Freq (%) | ORa | 95% CI | p value | ||
| Breast cancer | ||||||||||
| Functionally abnormal missense (HDR <1.2) | 84 | 82,372 | 0.11 | 24 | 123,464 | 0.02 | 5.25 | 3.34–8.39 | 1.63 × 10−15 | |
| Functionally abnormal missense (HDR 1.2–1.49) | 20 | 82,372 | 0.02 | 6 | 123,464 | 0.00 | 5.00 | 2.05–12.70 | 1.76 × 10−4 | |
| Functionally abnormal missense (HDR <1.49) | 104 | 82,372 | 0.13 | 30 | 123,464 | 0.02 | 5.2 | 3.47–7.9 | 9.99 × 10−19 | |
| Classified B or LB missense variants | 1,645 | 82,372 | 2.00 | 2,363 | 123,464 | 1.91 | 1.04 | 0.98–1.11 | 0.18 | |
| Classified P or LP missense variants | 103 | 82,372 | 0.13 | 30 | 123,464 | 0.02 | 5.15 | 3.43–7.83 | 1.88 × 10−18 | |
| Pathogenic missense standards | 53 | 82,372 | 0.06 | 9 | 123,464 | 0.01 | 8.83 | 4.34–18.37 | 2.07 × 10−13 | |
| DBD PTV | 211 | 82,372 | 0.26 | 37 | 123,464 | 0.03 | 8.56 | 6.03–12.36 | 1.37 × 10−48 | |
| Exon 11 PTV | 732 | 82,372 | 0.89 | 199 | 123,464 | 0.16 | 5.53 | 4.72–6.48 | 6.94 × 10−128 | |
| Ovarian cancer | ||||||||||
| Functionally abnormal missense (HDR < 1.2) | 22 | 10,960 | 0.2 | 24 | 123,464 | 0.02 | 10.34 | 5.69–18.43 | 1.25 × 10−12 | |
| Functionally abnormal missense (HDR 1.2–1.49) | 2 | 10,960 | 0.02 | 6 | 123,464 | 0.00 | 3.76 | 0.55–19.63 | 0.13 | |
| Functionally abnormal missense (HDR < 1.49) | 24 | 10,960 | 0.22 | 30 | 123,464 | 0.02 | 9.02 | 5.15–15.84 | 9.02 × 10−13 | |
| Classified B or LB missense variants | 232 | 10,960 | 2.13 | 2,363 | 123,464 | 1.91 | 1.11 | 0.97–1.27 | 0.14 | |
| Classified P or LP missense variants | 23 | 10,960 | 0.21 | 30 | 123,464 | 0.02 | 8.64 | 4.85–15.33 | 4.95 × 10−12 | |
| Pathogenic missense standards | 12 | 10,960 | 0.1 | 9 | 123,464 | 0.01 | 15.03 | 6.19–37.18 | 1.25 × 10−8 | |
| DBD PTV | 41 | 10,960 | 0.37 | 37 | 123,464 | 0.03 | 12.5 | 7.92–19.66 | 2.58 × 10−24 | |
| Exon 11 PTV | 221 | 10,960 | 2.02 | 199 | 123,464 | 0.16 | 12.63 | 10.38–15.33 | 3.07 × 10−124 | |
Cases: Ambry Genetics breast cancer or ovarian cancers; controls: gnomAD 2.1 and 3.1 non-cancer females and CARRIERS population-based controls.
a
OR, odds ratio calculated by Fisher’s exact test; HDR, homology directed repair; CI, confidence interval; Mut, number with variants of interest; Freq, frequency; DBD, DNA binding domain; PTV, protein truncating variant; P, pathogenic; LP, likely pathogenic; B, benign; LB, likely benign.