Introduction
Materials and methods
Breast cancer cohort
Inclusion criteria for analysis of BRCA1 and BRCA2
Total (n = 187) | Malay (n = 44) | Chinese (n = 118) | Indian (n = 22) | Others (n = 3) | |
---|---|---|---|---|---|
No. (%) | No. (%) | No. (%) | No. (%) | No. (%) | |
Age of onset of breast cancer in index case (years)
| |||||
20 to 29 | 14 (7) | 3 (7) | 10 (8) | 1 (5) | 0 (0) |
30 to 39 | 64 (34) | 21 (48) | 36 (31) | 6 (27) | 1 (33) |
40 to 49 | 49 (26) | 8 (18) | 35 (30) | 5 (23) | 1 (33) |
≥ 50 | 60 (32) | 12 (27) | 37 (31) | 10 (45) | 1 (33) |
Personal cancer history of breast, or breast and ovarian cancer
| |||||
Breast only | 182 (97) | 43 (98) | 117 (99) | 19 (86) | 3 (100) |
Both breast and/or ovarian | 5 (3) | 1 (2) | 1 (1) | 3 (14) | 0 (0) |
Bilateral breast cancer | 25 (13) | 6 (14) | 15 (13) | 4 (18) | 0 (0) |
Family history of breast and ovarian cancer in pedigree
| |||||
1 case (no family history) |
a73 (39) | 24 (54) | 40 (34) | 8 (36) | 1 (33) |
2 cases | 76 (41) | 13 (30) | 54 (46) | 9 (41) | 1 (33) |
3 cases | 24 (13) | 4 (9) | 17 (14) | 2 (9) | 0 (0) |
≥ 4 cases | 14 (7) | 3 (7) | 7 (6) | 3 (14) | 1 (33) |
Mutation detection
BOADICEA
Manchester Scoring System
Results
Mutation testing outcome
No. | Exon | Nucleotide change | AA change | Reported | Family (No.) | Ethnicity | |
---|---|---|---|---|---|---|---|
1 |
BRCA1
| 2 | 180 delA | STOP 22 |
Novel
| 1 | Indian |
2 | 2 | 185 delAG | STOP 39 | Ashkenazi Jews, others | 1 | Indian | |
3 | 2 | 185 insA | STOP 40 | Caucasian, European | 1 | Chinese | |
4 | 8 | 589 delCT | STOP 157 | Caucasian, Caribbean | 1 | Chinese | |
5 | 11 | 1100 delAT | STOP 328 | 1 | Chinese | ||
6 | 11 | 1173 G>T | E352X | Caucasian | 1 | Indian | |
7 | 11 | 1323 G>T | E402X |
Novel
| 1 | Malay | |
8 | 11 | 3889 delAG | STOP1265 | Various | 1 | Chinese | |
9 | 13 | 4377 C>T | Q1420X | Caucasian, African-American | 1 | Chinese | |
10 | 20 | 5370 C>T | R1751X | Various | 1 | Indian | |
11 | IVS 3+1 G>T |
Novel
| 1 | Chinese | |||
12 | IVS 3+2 delT |
Novel
| 1 | Chinese | |||
13 | IVS 4-1G>C |
Novel
| 1 | Indian | |||
14 | IVS 5-12 A>G | Various | 1 | Chinese | |||
1 |
BRCA2
| 3 | 490 delCT | STOP 99 |
Novel
| 2 | Malay |
2 | 10 | 1184 insA | STOP 326 | Caucasian | 1 | Chinese | |
3 | 10 | 2001 del4 | STOP 612 | Caucasian | 1 | Chinese | |
4 | 11 | 2699 del6 | STOP 824 |
Novel
| 1 | Malay | |
5 | 11 | 2864 delCT | STOP 879 |
Novel
| 1 | Chinese | |
6 | 11 | 4265 delCT | STOP 1350 | Filipino | 1 | Malay | |
7 | 11 | 6195 insA | STOP 2002 |
Novel
| 1 | Malay | |
8 | 11 | 6553 delGT | STOP 2109 |
Novel
| 1 | Chinese | |
9 | 11 | 6901 delA | STOP 2228 |
Novel
| 1 | Chinese | |
10 | 11 | 6943 G>T | E2239X |
Novel
| 1 | Chinese | |
11 | 22 | 9097 C>T | Q2957X |
Novel
| 1 | Indian | |
12 | 23 | 9326 insA | STOP 3042 | Various | 1 | Chinese | |
13 | IVS 17+1 G>A | Caucasian | 1 | Chinese |
No. | Exon | Nucleotide change | AA change | Reported | Family (No.) | Mutation classification | Ethnicity | |
---|---|---|---|---|---|---|---|---|
BRCA1
| 1 | 7 | 491 C>A | I124I |
Novel
| 1 | Benign? | Malay |
2 | 9 | 690 G>A | V191I | Various | 2 | Benign? | Chinese | |
3 | 11 | 873 C>T | R252C |
Novel
| 1 | Deleterious? | Malay | |
4 | 11 | 914 T>C | S265S |
Novel
| 1 | Benign? | Chinese | |
5 | 11 | 1155 C>T | P346S | Asian | 2 | Benign? | Chinese | |
6 | 11 | 2405 A>T | R762S | Chinese [8] | 1 | Benign? | Malay | |
7 | 11 | 2685 T>C | Y856H | Chinese | 6 | Benign? | Chinese | |
8 | 11 | 2845 A>T | N909I | Chinese | 1 | Benign? | Chinese | |
9 | 11 | 2858 T>A | N913K |
Novel
| 1 | Benign? | Chinese | |
10 | 11 | 3050 A>G | P977P |
Novel
| 1 | Benign? | Chinese | |
11 | 11 | 3781 A>C | E1221A |
Novel
| 1 | Benign? | Chinese | |
12 | 11 | 3922 A>G | N1268S |
Novel
| 1 | Benign? | Malay | |
13 | 16 | 5011 G>A | S1631N |
Novel
| 1 | Benign? | Chinese | |
14 | 24 | 5623 G>A | R1835Q |
Novel
| 1 | Benign? | Malay | |
15 | IVS 1-10 T>C | Various | 1 | Not clinically relevant [43] | Malay | |||
16 | IVS 12-10 G>A | Various | 1 | Deleterious? | Indian | |||
BRCA2
| 1 | 3 | 443 A>G | N72S |
Novel
| 1 | Benign? | Chinese |
2 | 5 | 668 A>G | Q147R | Asian, various | 2 | Benign? | 1 Malay, 1 Chinese | |
3 | 10 | 1171 T>A | C315S | Asian | 2 | Benign? | Chinese | |
4 | 10 | 1503 A>G | E425E |
Novel
| 1 | Benign? | Chinese | |
5 | 10 | 1590 A>G | K454K |
Novel
| 3 | Benign? | Chinese | |
6 | 10 | 1828 G>A | E534K |
Novel
| 1 | Deleterious? | Malay | |
7 | 10 | 1872 G>A | Q548Q | Various | 1 | Benign? | Chinese | |
8 | 10 | 1875 G>A | K549K |
Novel
| 1 | Benign? | Chinese | |
9 | 10 | 2053 C>G | Q609E |
Novel
| 1 | Benign? | Malay | |
10 | 11 | 2906 A>G | Q893R |
Novel
| 1 | Benign? | Malay | |
11 | 11 | 3648 T>C | S1140S | Chinese [8] | 1 | Benign? | Chinese | |
12 | 11 | 3673 A>G | M1149V | Asian, various | 3 | Benign? | 2 Malay, 1 Chinese | |
13 | 11 | 3903 A>G | T1225T |
Novel
| 1 | Benign? | Malay | |
14 | 11 | 4010 C>G | S1261C |
Novel
| 1 | Deleterious? | Malay | |
15 | 11 | 4806 A>G | T1526T |
Novel
| 1 | Benign? | Other | |
16 | 11 | 5395 A>C | T1723P |
Novel
| 1 | Benign? | Malay | |
17 | 11 | 5540 G>A | G1771D | Various | 1 | Not clinically relevant [BIC] | Malay | |
18 | 11 | 5863 G>A | E1879K | Caucasian | 1 | Benign? | Indian | |
19 | 11 | 6013 A>G | I1929V | Asian, various | 1 | Not clinically relevant [BIC] | Chinese | |
20 | 11 | 6550 C>T | R2108C | Various | 3 | Benign? | 2 Malay, 1 Chinese | |
21 | 12 | 7157 C>A | T2310N |
Novel
| 1 | Deleterious? | Indian | |
22 | 17 | 8169 A>C | L2647L |
Novel
| 1 | Benign? | Malay | |
23 | 18 | 8415 G>T | K2729N | Asian, various | 1 | Not clinically relevant [44] | Chinese | |
24 | 19 | 8584 G>A | A2786T |
Novel
| 1 | Deleterious? | Chinese | |
25 | 21 | 8930 G>A | G2901D | Asian | 1 | Deleterious? | Chinese | |
26 | 23 | 9332 A>G | Y3035C | Caucasian | 1 | Deleterious? | Chinese | |
27 | 23 | 9334 C>G | Q3036E |
Novel
| 1 | Benign? | Chinese | |
28 | 27 | 10135 A>T | S3303C |
Novel
| 1 | Deleterious? | Other | |
29 | 27 | 10462 A>G | I3412V | Various | 1 | Not clinically relevant [45] | Chinese | |
30 | IVS 2-7T>A | Caucasian | 1 | Deleterious? | Malay | |||
31 | IVS 7-10 insT |
Novel
| 1 | Deleterious? | Other |
Ethnicity | Total families | Families with deleterious mutation | Families with unclassified variant | ||
---|---|---|---|---|---|
BRCA1
|
BRCA2
|
BRCA1
|
BRCA2
| ||
Malay
| 44 | 1 | 5 | 6 | 14 |
Chinese
| 118 | 8 | 8 | 15 | 18 |
Indian
| 22 | 5 | 1 | 1 | 2 |
Others
| 3 | 0 | 0 | 0 | 3 |
Total
|
187
|
14
|
14
|
22
|
37
|
Clinical presentation of breast cancer
Nucleotide change | AA change | Age of diagnosis of breast cancer | No. of breast/ovarian cancers in family | Mean age diagnosis (Breast cancer) | No. of cases (Breast cancer ≤ 50) | ER | PR | HER2 | Grade | ||
---|---|---|---|---|---|---|---|---|---|---|---|
BRCA1
| 180 delA | STOP 22 | 55 | 2 | 43 | 1 | - | - | - | 2 | IDC |
185 delAG | STOP 39 | 33 | 1 | 33 | 1 | - | - | - | 3 | IDC | |
185 insA | STOP 40 | 57 | 7 | 44 | 4 | NA | NA | NA | NA | IDC | |
589 delCT | STOP 157 | 45 | 3 | 41 | 3 | - | - | - | NA | IDC | |
1100 delAT | STOP 328 | 28 | 2 | 28 | 1 | - | - | - | 3 | IDC | |
1173 G>T | E352X | 45 | 3 | 45 | 1 | - | - | - | 2 | IDC | |
1323 G>T | E402X | 34 | 3 | 31 | 2 | NA | NA | NA | NA | Sarcoma | |
3889 delAG | STOP1265 | 47 | 3 | 47 | 2 | - | NA | + | NA | DCIS/IDC | |
4377 C>T | Q1420X | 39 | 2 | 45 | 2 | - | - | +/- | 3 | IDC | |
5370 C>T | R1751X | 31 | 5 | 38 | 3 | NA | NA | NA | NA | NA | |
IVS 3+1 G>T | 46 | 2 | 47 | 2 | - | NA | + | NA | IDC | ||
IVS 3+2 delT | 32 | 2 | 56 | 1 | - | NA | - | 2 | IDC | ||
IVS 4-1G>C | 39 | 2 | 48 | 1 | NA | NA | NA | NA | IDC | ||
IVS5-12 A>G | 33 | 1 | 33 | 1 | - | - | - | 3 | IDC | ||
BRCA2
| 490 delCT | STOP 99 | 39 | 2 | 56 | 1 | - | - | - | 2 | IDC |
490 delCT | STOP 99 | 51 | 4 | 45 | 3 | + | + | - | NA | ILC | |
1184 insA | STOP 326 | 34 | 1 | 34 | 1 | + | + | - | 2 | IDC | |
2001 del4 | STOP 612 | 37 | 1 | 37 | 1 | + | - | + | 3 | IDC | |
2699 del6 | STOP 824 | 41 | 2 | 57 | 1 | + | NA | NA | 2 | IDC | |
2864 delCT | STOP 879 | 40 | 1 | 40 | 1 | - | NA | NA | 3 | IDC | |
4265 delCT | STOP 1350 | 55 | 4 | 44 | 3 | + | + | - | 2 | IDC | |
6195 insA | STOP 2002 | 42 | 3 | 46 | 2 | NA | NA | NA | NA | NA | |
6553 delGT | STOP 2109 | 59 | 3 | 49 | 1 | + | NA | - | 2 | IDC | |
6901 delA | STOP 2228 | 35 | 1 | 35 | 1 | NA | NA | NA | NA | IDC/DCIS | |
6943 G>T | E2239X | 47 | 2 | 44 | 2 | NA | NA | NA | NA | NA | |
9097 C>T | Q2957X | 38 | 7 | 44 | 2 | NA | NA | NA | NA | NA | |
9326 insA | STOP 3042 | 56 | 4 | 49 | 2 | - | - | NA | NA | NA | |
IVS 17+1 G>A | 36 | 2 | 46 | 1 | - | - | - | 3 | IDC |
Overall |
BRCA1
|
BRCA2
| Non-BRCA
| |
---|---|---|---|---|
Age of onset | 22 to 78 | 28 to 57 | 34 to 59 | 22 to 78 |
Average age of onset (years) | 41.9 | 40.3 | 43.6 | 44.2 |
Total no. of breast and ovarian cancers in family | 1 to 7 | 1 to 7 | 1 to 7 | 1 to 6 |
Average no. of breast and ovarian cancers in family | 1.9 | 2.7 | 2.6 | 1.8 |
No. of cases of breast cancer <50 | 0 to 4 | 1 to 3 | 1 to 3 | 0 to 4 |
Average no. of cases of breast cancer <50 | 1.1 | 1.6 | 1.5 | 1.0 |
% with ER-negative tumours | 48% | 100% | 40% | 45% |
Prediction of BRCA1/BRCA2carrier status based on risk factors
Personal history | Family history | Total |
BRCA1positive |
BRCA2positive |
BRCApositive |
BRCApositive |
---|---|---|---|---|---|---|
Number | Number | Number | % | |||
Breast cancer <50 years | Nil | 61 | 2 | 3 | 5 | 8.2 |
Breast cancer <50 years | 1 breast cancer <50 years | 29 | 1 | 3 | 4 | 13.8 |
Breast cancer ≥ 50 years | 1 breast cancer <50 years | 13 | 1 | 0 | 1 | 7.7 |
Breast cancer at any age | ≥ 2 breast cancer <50 years | 7 | 1 | 0 | 1 | 14.3 |
Breast cancer at any age | ≥ 3 breast cancer at any age | 9 | 0 | 3 | 3 | 33.3 |
Breast cancer at any age | ≥ 1 ovarian cancer at any age | 10 | 4 | 1 | 5 | 50.0 |
Breast and ovarian cancer | Any | 5 | 2 | 1 | 3 | 60.0 |
Bilateral breast cancer | Any | 25 | 4 | 1 | 5 | 20.0 |
Risk prediction models (BOADICEA) and scoring methods (Manchester Scoring System)
Manchester Scoring System | BOADICEA | |||||
---|---|---|---|---|---|---|
BRCA1
|
BRCA2
| Combined |
BRCA1
|
BRCA2
| Combined | |
Area under the receiver operating curves
| 0.74 | 0.82 | 0.80 | 0.82 | 0.56 | 0.73 |
Standard error
| 0.078 | 0.079 | 0.06 | 0.070 | 0.093 | 0.061 |
95% CI
| 0.67 – 0.81 | 0.75 – 0.88 | 0.72 – 0.86 | 0.75 – 0.88 | 0.48 – 0.64 | 0.65 – 0.80 |
P value
a
| 0.0018 | 0.0001 | 0.0001 | 0.0001 | 0.507 | 0.0001 |
Sensitivity
| 57% | 55% | 72% | 57% | 9% | 40% |
Specificity
| 76% | 87% | 74% | 93% | 93% | 85% |
Positive-predictive value
| 20% | 25% | 37% | 47% | 10% | 36% |
Negative-predictive value
| 94% | 96% | 93% | 95% | 93% | 87% |