Table 2.

Burden-type cancer risk association analysis for human CHEK2 variants.

Variant group based on function	Aa change	Cases	Controls	OR (95% CI), P (population-based studies)	OR (95% CI), P (all studies)
Functional VUS	p.I157S	1	0	1.13 (0.87–1.46), P = 0.378	0.97 (0.76–1.23), P = 0.7943
	p.R181H	33	22
	p.N186H	17	14
	p.V200A	0	1
	p.C243R	4	8
	p.H371Y	37	38
	p.N446D	4	3
	p.P509S	21	22
Intermediate VUS	p.E64K	53	31	1.63 (1.21–2,.20), P = 0.0014	1.79 (1.36–2.36), P < 0.0001
	p.K141T	1	0
	p.D203G	4	0
	p.E239K	12	7
	p.D438Y	26	27
	p.I448S	1	3
	p.A480T	4	0
	p.R521W	9	2
Intermediate VUS (excl. p.E64K)				1.52 (1.01–2.28), P = 0.0448	1.81 (1.25–2.62), P = 0.0016
Damaging VUS	p.R117G	47	22	2.23 (1.62–3.07), P < 0.0001	3.03 (2.25–4,08), P < 0,0001
	p.F125S	0	1
	p.S140N	1	0
	p.R145W	10	9
	p.I160T	0	1
	p.G167R	8	3
	p.F169L	1	2
	p.G229S	0	1
	p.A230P	n/a	n/a
	p.A247D	1	0
	p.K249R	n/a	n/a
	p.I251F	3	0
	p.E273K	n/a	n/a
	p.G306E	1	0
	p.L326P	1	0
	p.R346H	4	2
	p.D347N	4	3
	p.E351D	7	2
	p.G386R	1	0
	p.Y390C	n/a	n/a
	p.Y390S	2	3
	p.A392V	12	4
	p.D409N	1	1
	p.S412R	1	0
	p.G414E	1	0
	p.P426R	1	0
	p.R474H	11	0
	p.W485G	0	1
Damaging VUS (excl. p.R117G)				2.23 (1.48–3.38), P < 0.0001	3.09 (2.11–4.53), P < 0.0001

Note: Variants with similar impact of CHK2 functionality were grouped (Fig. 2C). Only missense variants for which case–control frequencies from population- or family-based studies have been reported were included (7). The case–control frequencies reflect those of the population-based studies alone. The analysis was also performed for groups of CHEK2 variants without p.E64K or p.R117G, for which the carrier frequencies are high.

Abbreviation: n/a, not available.