Table 4.
Risks Associated With Specific Binding Domains: Comparison of Mutations Not in the Domain (ie, the Reference Group) vs Those Within the Domain
| Gene | Domain | Binding Partner |
Region | Breast Cancer
|
Ovarian Cancer
|
||||
|---|---|---|---|---|---|---|---|---|---|
| No. With/Without Mutationa |
HR (95% CI) | FDR P Value |
No. With/Without Mutationa |
HR (95% CI) | FDR P Value |
||||
| BRCA1 | RING | BARD1 | c.72–192 | 781/595 | 1.13 (1.02–1.26)b,c | .04 | 205/1171 | 0.81 (0.67–0.97) | .07 |
|
| |||||||||
| Coiled coil | PALB2 | c.3759–3819 or c.4191–4272 |
122/90 | 1.20 (0.93–1.54)d | .16 | 39/173 | 0.97 (0.62–1.50) | .88 | |
|
| |||||||||
| BRCT | BACH1 | c.4926–5169 or c.5268–5526 |
1203/832 | 1.26 (1.15–1.38)e,f | <.001 | 298/1737 | 0.86 (0.74–1.01) | .09 | |
|
| |||||||||
| BRCA2 | BRC | RAD51 | c.3006–3108, c.3636–3738, c.4263–4365, c.4551–4653, c.4992–5094, c.5511–5613, c.5913–6015, or c.6153–6255 |
810/992 | 0.67 (0.56–0.79)g,h | <.001 | 205/1597 | 1.09 (0.78–1.53) | .77 |
|
| |||||||||
| DNA binding |
c.7437–8001 | 464/336 | 1.17 (0.99–1.38) | .08 | 63/737 | 1.06 (0.71–1.59) | .77 | ||
|
| |||||||||
| OB folds | ssDNA | c.8010–8400 or c.9156–9570 |
512/364 | 1.18 (1.01–1.37)h,i | .07 | 50/826 | 0.57 (0.39–0.84) | .02 | |
|
| |||||||||
| Tower | RAD51 | c.8443–8616 | 193/154 | 1.20 (0.92–1.56) | .19 | 18/329 | 0.42 (0.18–1.00)j | .10 | |
Abbreviations: FDR, false discovery rate; HR, hazard ratio; NMD, nonsense-mediated decay; OB, oligonucleotide-binding.
Among 19 581 carriers of BRCA1 mutations and 11 900 carriers of BRCA2 mutations.
Missense mutations only: HR = 1.42; 95% CI, 1.06–1.90.
Mutations conferring NMD only: HR = 2.56; 95% CI, 1.03–6.34.
Mutations conferring NMD only: HR = 1.35; 95% CI, 1.05–1.72.
Premature termination codon mutations only: HR = 1.31; 95% CI, 1.17–1.47.
Mutations conferring NMD only: HR = 1.38; 95% CI, 1.20–1.59.
Premature termination codon mutations only contributed to this estimate.
Mutations conferring NMD only: HR = 1.26; 95% CI, 1.07–1.48.
Premature termination codon mutations only: HR = 1.26; 95% CI, 1.07–1.48.
Mutations conferring NMD only: HR = 0.31; 95% CI, 0.13–0.77.