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 4 Severity scores applied to selected classes of potentially pathogenic rare variants

Class	Binary	Graded	#Variants	Cases, n	Controls, n
	severity	severity
Truncating and spliceogenic variants
Frameshift, excluding the last exon	1.0	6.0	4	2	3
Nonsense, excluding the last exon	1.0	6.0	3	3	0
Severe acceptor damage	1.0	5.7	1	1	0
Moderate acceptor damage	1.0	2.4	0	0	0
Severe donor damage	1.0	5.7	1	1	0
Moderate donor damage	1.0	2.4	2	2	0
Missense
Key domain rMS, graded C0	0.0	0.0	4	4	1
Key domain rMS, graded C15	1.0	1.0	1	1	0
Key domain rMS, graded C25	1.0	2.0	6	6	1
Key domain rMS, graded C35	1.0	3.0	1	0	1
Key domain rMS, graded C45	1.0	4.0	3	3	0
Key domain rMS, graded C55	1.0	5.0	0	0	0
Key domain rMS, graded C65	1.0	6.0	8	10	1
Key domain in-frame deletion^†	1.0	6.0	1	0	1

^†Includes the RAD50 final exon truncating variant c.3852del4, which falls within the C-terminal ATPase domain (a key domain), which we consider analytically equivalent to a key domain rMS graded C65. rMS, rare missense substitution.

ISSN: 1465-542X