Rare key functional domain missense substitutions in MRE11A, RAD50, and NBNcontribute to breast cancer susceptibility: results from a Breast Cancer Family Registry case-control mutation-screening study

Table 9 Individual contributions of MRE11A , RAD50 , and NBN to the ensemble model

Class	Cases, n	Controls, n	Crude OR^†(95% CI)	Adjusted OR^†(95% CI)
Noncarriers	1,283	1,114
MRE11A
T + SJV^¥	1	0	^∞[P = 1.00]^¥
rMS or IFD^*¢	7	1	6.08 (0.75-49.5)	3.62 (0.42-31.5)
Combined	8	1	6.95 (0.87-55.6)	5.02 (0.59-42.8)
RAD50
T + SJV^¥$	4	3	1.16 (0.26-5.18)	1.09 (0.23-5.24)
rMS or IFD^*	10	2	4.34 (0.95-19.9)	3.21 (0.68-15.2)
Combined	14	5	2.43 (0.87-6.77)	1.98 (0.68-5.71)
NBN
T + SJV^¥	4	0	^∞[P = 0.13]^¥
rMS or IFD^*	3	1	2.60 (0.27-25.1)	2.12 (0.20-22.6)
Combined	7	1	6.08 (0.75-49.5)	5.28 (0.62-45.2)
MRE11A, RAD50, and NBN ensemble model^*
T + SJV^¥$	9	3	2.60 (0.70-9.65)	2.61 (0.67-10.1)
rMS or IFD^*¢	20	4	4.34 (1.48-12.7)	3.07 (1.01-9.31)
Combined	29	7	3.60 (1.57-8.24)	2.88 (1.22-6.78)

Boldface within the table indicates P <0.05. ^†In these binary logistic regressions, the regression coefficient = ln(OR). ^¥Truncating and splice junction variants; excludes final exon nonsense and frameshift variants. ^¥Because there were no observations of this class of variants in the controls, the crude odds ratio is infinity (∞) and the P value was calculated by Fisher exact test rather than by logistic regression; this also precludes calculation of adjusted odds ratios. As 95% confidence intervals could not be estimated, we report the P value. ^*Key functional domain rare missense substitutions with A-GVGD scores > C0, in-frame indels, and final exon nonsense and frameshift variants if they also fall in a key functional domain. The key functional domains are defined in Figure 1. ^¢One subject (a case) carried both the MRE11A key domain rare missense substitution MRE11A p.D235G and the NBN non key domain rare missense substitution NBN p.V210F. ^$One subject (a case) carried both the RAD50 splice acceptor variant RAD50 c.552-1G > A and the RAD50 silent substitution RAD50 c.3153G > A (p.L1051L). T + SJV, truncating and splice junction variants; rMS, rare missense substitution; IFD, in-frame deletion.

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