Supplementary Table 1 Clinical characteristics of BRCA1/2 carriers including index cases in the Northern Netherlands (study population) and in the rest of the Netherlands (reference population)

Characteristics / BRCA1 carriers / BRCA2 carriers
Northern Netherlands
N = 656 / Rest of the Netherlands
N = 1580 / p-value / Northern Netherlands
N = 394 / Rest of the Netherlands
N = 433 / p-value
Families
N
Number carriers per family, median (IQR) / 220
2 (1-4) / 575
2 (1-3) / 0.080 / 142
2 (1-4) / 174
2(1-3) / 0.059
Age at last follow-up, mean (SD) / 48.5 (13.3) / 42.7 (11.4) / <0.001 / 49.9 (13.5) / 45.0 (11.4) / <0.001
Primary breast cancer
N (%)
Age, mean (SD)
Above age 60, N (% of all breast cancers) / 304 (47%)
42.4 (10.1)
20 (7%) / 714 (45%)
40.2 (8.5)
16 (2%) / 0.608
0.001
0.001 / 174 (44%)
47.1 (10.6)
27 (16%) / 183 (42%)
43.4 (8.6)
9 (5%) / 0.622
<0.001
0.001
Ovarian cancer
N (%)
Age, mean (SD) / 136 (21%)
50.6 (9.3) / 153 (10%)
51.4 (9.2) / <0.001
0.449 / 43 (11%)
56.7 (9.6) / 34 (8%)
54.9 (10.1) / 0.121
0.435
RRM
Number (%)
Age, mean (SD) / 130 (20%)
41.3 (9.4) / 259 (16%)
41.1 (9.6) / 0.050
0.831 / 58 (15%)
42.9 (8.1) / 53 (12%)
42.1 (7.7) / 0.307
0.600
RRSO
N (%)
Age, mean (SD) / 214 (33%)
45.4 (8.6) / 355 (23%)
44.8 (8.3) / <0.001
0.420 / 126 (32%)
47.9 (9.1) / 80 (19%)
46.6 (8.4) / <0.001
0.302

Abbreviations:IQR: interquartile range, RRM: risk-reducing mastectomy; RRSO: risk-reducing salpingo-oophorectomy; RRSO: risk-reducing salpingo-oophorectomy

Supplementary Table 2 Overview of number of carriers (excluding index cases) at risk at each age-decade and number of breast cancer event for each age-decade

Age / BRCA1 carriers / BRCA2 carriers
Northern Netherlands / Rest of the Netherlands / Northern Netherlands / Rest of the Netherlands
N
(N of event) / Incidence
(95%CI) / N
(N of event) / Incidence
(95%CI) / N
(N of event) / Incidence
(95%CI) / N
(N of event) / Incidence
(95%CI)
20-30 / 64 (10) / 15.6 (8.7-27.1) / 159 (37) / 23.3 (17.5-30.7) / 34 (1) / 2.9 (0.0-19.1) / 26 (2) / 7.7 (2.0-27.4)
30-40 / 142 (48) / 33.8 (26.7-42.2) / 410 (153) / 37.3 (32.8-42.2) / 65 (13) / 20.0 (12.1-31.9) / 99 (30) / 30.3 (22.3-40.4)
40-50 / 133 (52) / 39.1 (31.4-47.9) / 301 (128) / 42.5 (37.2-48.3) / 76 (27) / 35.5 (25.9-47.4) / 98 (40) / 40.8 (31.8-51.2)
50-60 / 64 (21) / 32.8 (22.8-45.8) / 136 (42) / 30.9 (23.9-39.4) / 55 (18) / 32.7 (22.0-46.8) / 52 (19) / 36.5 (25.1-51.1)
60-70 / 37 (9) / 24.3 (13.5-41.5) / 47 (9) / 19.2 (10.5-33.6) / 27 (10) / 37.0 (21.9-57.9) / 16 (3) / 18.8 (6.5-47.5)
70-75 / 24 (1) / 4.2 (0.6-26.1) / 25 (2) / 8.0 (2.1-28.4) / 11 (1) / 9.1 (1.3-49.2) / 7 (0) / -

Supplementary Table 3Cumulative incidence of breast cancer in BRCA1/2 carriers, excluding index cases, in the study population (Northern Netherlands) and reference population (rest of the Netherlands). Estimation of risks weighted to an equal contribution from the different birth cohorts in each population.

Age (years) / BRCA1 carriers / BRCA2 carriers
Northern Netherlands / Rest of the Netherlands / Northern Netherlands / Rest of the Netherlands
N = 467 / N = 1091 / N = 269 / N = 305
≤30 / 2.1 (1.0-4.4) / 3.1 (1.8-5.3) / 0.4 (0.0-4.3) / 0.4 (0.0-3.9)
≤40 / 11.5 (8.3-15.8) / 17.6 (14.1-21.9) / 7.5 (4.3-13.0) / 10.3 (6.4-16.4)
≤50 / 31.1 (25.6-37.4) / 37.0 (32.0-42.5) / 28.1 (21.2-36.7) / 26.8 (20.0-35.4)
≤60 / 44.0 (37.4-51.1) / 52.4 (46.5-58.5) / 48.8 (39.5-58.9) / 44.7 (36.0-54.4)
≤70 / 50.9 (43.6-58.7) / 58.7 (52.4-65.1) / 64.3 (53.5-75.0) / 52.6 (43.0-62.9)
≤75 / 53.1 (45.3-61.3) / 63.4 (56.7-70.2) / 68.0 (56.5-79.0) / -

Supplementary Table4Relative risks (hazard ratios (95% confidence interval)) of breast cancer for mutation spectrum, excluding index cases

BRCA1
Referencea
mutations / The Netherlands b / Northern Netherlands c / Rest of the Netherlands c
5’
N = 394 / OCCR
N = 382 / 3’
N = 604 / 5’
N = 116 / OCCR
N = 182 / 3’
N = 169 / 5’
N = 278 / OCCR
N = 200 / 3’
N = 435
5’ / NA / 1.04
(0.79-1.36) / 1.33*
(1.06-1.68) / NA / 0.76
(0.50-1.16) / 1.06
(0.70-1.61) / NA / 1.26
(0.88-1.80) / 1.47*
(1.12-1.94)
OCCR / 0.97
(0.73-1.27) / NA / 1.29*
(1.01-1.64) / 1.32
(0.86-2.02) / NA / 1.39
(0.95-2.06) / 0.79
(0.56-1.13) / NA / 1.17
(0.85-1.60)
3’ / 0.78*
(0.61-0.99) / 0.75*
(0.60-0.94) / NA / 0.94
(0.62-1.43) / 0.72
(0.49-1.06) / NA / 0.68*
(0.52-0.90) / 0.86
(0.63-1.17) / NA
BRCA2
Referencea
mutations / The Netherlands b / Northern Netherlands c / Rest of the Netherlands c
5’
N = 105 / OCCR
N = 200 / 3’
N = 194 / 5’
N = 73 / OCCR
N = 48 / 3’
N = 148 / 5’
N = 32 / OCCR
N = 152 / 3’
N = 45
5’ / NA / 0.44*
(0.27-0.70) / 0.72
(0.48-1.10) / NA / 0.43*
(0.20-0.91) / 0.55*
(0.33-0.91) / NA / 0.53
(0.27-1.05) / 1.22
(0.58-2.57)
OCCR / 2.29*
(1.43-3.68) / NA / 1.66*
(1.05-2.62) / 2.35*
(1.10-5.01) / NA / 1.28
(0.61-2.69) / 1.89
(0.95-3.75) / NA / 2.30*
(1.30-4.06)
3’ / 1.39
(0.91-2.10) / 0. 60*
(0.38-0.96) / NA / 1.83*
(1.10-3.04) / 0.78
(0.37-1.63) / NA / 0.82
(0.39-1.73) / 0.44*
(0.25-0.77) / NA

Abbreviations:NA: not applicable

a The BRCA1 OCCR was defined as nucleotides 2282 to 4071, and the BRCA2 OCCR as nucleotides 2831 to 6401 (10, 17, 18). The regions downstream and upstream of the OCCR were defined as the first nucleotide at the prime side up to the nucleotide before the start of the OCCR. The categories listed as the reference mutations are the reference category in the Cox regression model.

b Adjusted for region and birth year

cAdjusted for birth year,

* Significant (p<0.05)

Supplementary Table 5 Regional differences in the breast cancer risk of BRCA1/2 carriers including index cases (adjusted for birth year) in the Netherlands: the study population (Northern Netherlands) compared to the reference population (the rest of the Netherlands)

Model / Regional differences
BRCA1 / BRCA2 <60 / BRCA2 ≥60
N (events) / HR (95% CI) / N (events) / HR (95% CI) / N (events) / HR (95% CI)
Region
Reference population
Study population / 1580 (711)
656 (279) / 1
0.66 (0.58-0.77) / 433 (171)
394 (142) / 1
0.62 (0.49-0.78) / 40 (9)
58 (25) / 1
2.56 (1.91-5.48)
Region a
Reference population
Study population / 1384 (612)
656 (279) / 1
0.67 (0.57-0.77) / 359 (147)
394 (142) / 1
0.61 (0.47-0.77) / 31 (9)
58 (25) / 1
2.02 (0.94-4.34)
Region a corrected for OCCR
Reference population
Study population / 1384 (612)
656 (279) / 1
0.69 (0.59-0.80) / 359 (147)
394 (142) / 1
0.46 (0.35-0.61) / 31 (9)
58 (25) / 1
1.88 (0.80-4.41)

a Including only carriers with known mutation spectrum

1