Table 2.
Mutation-Specific Risk Groups: Risks Relative to Noninsertion or Nondeletion Exon 11 Mutations
| Group | Description | Mutation Types Included | NMD | Protein | No. (%) With Mutation | Breast Cancer, HR (95% CI) | No. of Women With Breast Cancer | Ovarian Cancer, HR (95% CI) | No. of Women With Ovarian Cancer |
|---|---|---|---|---|---|---|---|---|---|
| BRCA1 (n = 19 581) | |||||||||
| a | Exon 11 nonsense mutations | NS | Yes | No | 1770 (9.0) | 1 [Reference] | 796 | 1 [Reference] | 336 |
| 1 | NMD | FS, NS, OF-GR, OF-SP | Yes | No | 11 027 (56.3) | 1.20 (1.08–1.33) | 5469 | 0.94 (0.80–1.11) | 2038 |
| 2 | All premature termination mutations | FS, NS, OF-GR, OF-SP | Yes | No | 14 453 (73.8) | 1.25 (1.12–1.38) | 7318 | 0.93 (0.79–1.09) | 2524 |
| 3 | Mutations before c.297 ATG presumed transcription reinitiation | FS, NS | No | No | 2763 (14.1) | 1.40 (1.12–1.74) | 250 | 0.66 (0.46–0.95) | 74 |
| 4 | Not premature termination | MS, IF, GR, IF-SP, FS | No | Yes | 5398 (27.6) | 1.51 (1.34–1.70) | 2986 | 0.73 (0.61–0.88) | 781 |
| 5 | All founder mutations | FS | 5375 (27.5) | 1.41 (1.23–1.61) | 2698 | 0.72 (0.60–0.88) | 850 | ||
| 5a | Founder mutation c.68_69delAG | FS | No | 2324 (11.9) | 1.14 (0.94–1.38) | 1033 | 0.67 (0.51–0.87) | 391 | |
| 5b | Founder mutation c.5266dupC | FS | Yes | 3051 (15.6) | 1.63 (1.41–1.89) | 1665 | 0.73 (0.57–0.92) | 459 | |
| 6 | All missense mutations | MS | Yes | 1620 (8.3) | 1.40 (1.20–1.64) | 899 | 0.73 (0.57–0.92) | 241 | |
| 6a | Missense mutations in RING domain (c.72–192) | MS | Yes | 1213 (6.2) | 1.56 (1.32–1.84) | 681 | 0.73 (0.56–0.96) | 171 | |
| 6b | Missense mutations in BRCT domain (c.4866–5325) | MS | Yes | 372 (1.9) | 1.09 (0.82–1.45) | 202 | 0.72 (0.48–1.09) | 64 | |
| 7 | Missense mutations and in-frame deletions | MS+IF, IF-SP, IF-GR | Yes | 1658 (8.5) | 1.42 (1.22–1.66) | 925 | 0.71 (0.56–0.91) | 249 | |
| 8 | In-frame deletions (splice, single codon, large deletion) | IF, IF-SP, IF-GR | Yes | 38 (0.2) | 2.41 (1.41–4.11) | 26 | 0.51 (0.15–1.76) | 8 | |
| 9 | All premature termination codons not leading to NMD | FS, NS, OF-SP, OF-GR | No | Yes | 3663 (18.7) | 1.58 (1.38–1.80) | 2000 | 0.74 (0.60–0.91) | 520 |
| BRCA2 (n = 11 900) | |||||||||
| a | Exon 11 nonsense mutations | NS | Yes | No | 1001 (8.4) | 1 [Reference] | 534 | 1 [Reference] | 155 |
| 1 | NMD | FS, NS, OF-GR, OF-SP | Yes | No | 9961 (83.7) | 1.10 (0.95–1.27) | 5383 | 0.78 (0.56–1.08) | 803 |
| 2 | Not premature termination codon | IF-S, IF-FS, NS | No | Yes | 203 (1.7) | 1.35 (0.92–1.97) | 118 | 0.34 (0.13–0.88) | 12 |
| 3 | In-frame deletions (splice, frame shift) | IF-FS, IF-S | No | Yes | 117 (1.0) | 1.41 (0.85–2.35) | 76 | 0.26 (0.08–0.88) | 9 |
| 4 | Premature termination codons in last exon not leading to NMD | FS, NS | No | Yes | 86 (0.7) | 1.32 (0.79–2.19) | 42 | 0.51 (0.13–2.09) | 3 |
| 5 | Founder mutation c.5946delT | 1341 (11.3) | 0.79 (0.60–1.03) | 579 | 0.77 (0.46–1.32) | 155 | |||
Abbreviations: FS, frame shift; GR, genomic rearrangement; HR, hazard ratio; IF, in-frame; NE, not estimable; NMD, nonsense-mediated decay; NS, nonsense; MS, missense; OF, out of frame; SP, splicing.