Background
Methods
Patients
Point mutation screening
Investigation of BRCA1/2CNVs by MLPA
Classification of variants
Transcript analysis
Screening of copy number alterations via array comparative genomic hybridization (array-CGH)
Gene dosage qPCR
Results
Screening of BRCA1/2: point mutations and copy number variations; CHEK2 1100delC and TP53R337H
Proband | Age of onset | Tumor | Clinical criteria | Gene | Alteration | Mutation type | Exon | Reference |
---|---|---|---|---|---|---|---|---|
SM-01
|
39
| Breast | HBOC |
BRCA1
| c.5203delTT | Frameshift | 18 | BIC |
SM-17
|
49/51
| Ovarian/Breast | HBOC |
BRCA1
| c.3376 T > G; p.L1086X | Nonsense | 11 | BIC |
SM-25
|
69
| Breast | HBOC |
BRCA1
| c.120A > G; p.M1V | Missense | 2 | BIC |
SM-69
|
33
| Breast | HBOC |
BRCA1
| c.5242C > A; p.A1708E | Missense | 18 | BIC |
SM-74
|
50
| Hemangioblastoma | HBOC |
BRCA1
| c.2080delA | Frameshift | 11 | BIC |
MO-07
|
34
| Breast | HBOC |
BRCA1
| c.5382insC | Frameshift | 20 | BIC |
MO-09
|
42
| Breast | HBOC |
BRCA1
| c.5382insC | Frameshift | 20 | BIC |
MO-45
|
48
| Breast | HBOC |
BRCA1
| c.5382insC | Frameshift | 20 | BIC |
MO-13
|
32/44
| Breast/Skin | HBOC |
BRCA1
| c.4831del5 | Frameshift | 16 | BIC |
MO-26
|
37
| Breast | HBOC |
BRCA1
| c.1499insA | Frameshift | 11 | BIC |
MO-31
|
38/63
| Breast/Peritoneal | HBOC |
BRCA1
| c.5563G > A; p.W1815X | Nonsense | 23 | BIC |
MO-37
|
(-)
| Breast | HBOC |
BRCA1
| c.3759G > T; p.E1214X | Nonsense | 11 | BIC |
MO-38
|
42/44
| Breast/Breast | HBOC |
BRCA1
| c.307 T > A; p.L63X | Nonsense | 5 | BIC |
SM-50
|
36/47
| Breast/Breast | HBOC |
BRCA1
| c.4794 + 1G > A | Splice site | 15 | BIC |
SM-80
|
42/48
| Breast/Ovarian | HBOC |
BRCA1
| c.1446 A > T; p.K443X | Nonsense | 11 | Current study |
SM-81
|
55
| Fallopian Tube | HBOC |
BRCA1
| c.5582insT | Frameshift | 23 | Current study |
SM-89
|
40
| Breast | HBOC |
BRCA1
| c.4406 C > A; p.Y1429X | Nonsense | 13 | Current study |
MO-15
|
43/56
| Breast/Ovarian | HBOC |
BRCA1
| c.560 + 2 T > A | Splice site | 7 | Carraro et al. [28] |
M0-28
|
48
| Breast | HBOC |
BRCA1
| Exon 24 amplification | LGR | 24 | Current study |
SM-03
|
36/36
| Breast/Ovarian | HBOC |
BRCA1
| Exon 16–17 deletion | LGR | 16-17 | BIC |
SM-08
|
33
| Breast | HBOC |
BRCA2
| c.6174delT | Frameshift | 11 | BIC |
SM-46
|
32
| Breast | HBOC |
BRCA2
| c.9709 A > T; p.K3161X | Nonsense | 25 | BIC |
SM-61
|
51
| Breast | HBOC |
BRCA2
| c.9709A > T; p.K3161X | Nonsense | 25 | BIC |
SM-104
|
32
| Breast | HBOC |
BRCA2
| c.3034del4 | Frameshift | 11 | BIC |
MO-02
|
53/63
| Breast/Breast | HBOC |
BRCA2
| c.9610C > T, p.R3128X | Nonsense | 25 | BIC |
SM-53
|
30/49
| Breast/Thyroid | HBOC |
BRCA2
| c.6242del4 | Frameshift | 11 | Current study |
SM-84
|
35
| Breast | HBOC |
BRCA2
| c.8423 T > G; p.L2732X | Nonsense | 18 | Current study |
MO-41
|
47
| Breast | HBOC |
CHEK2
| c.1100delC; p.Thr367MetfsX15 | Frameshift | 10 | BIC |
SM-31
|
49
| Breast | HBOC |
TP53
| c.1010G > A; p.R337H | Missense | 10 | IARC TP53 |
SM-31
|
49
| Breast | HBOC |
TP53
| c.1010G > A; p.R337H | Missense | 10 | IARC TP53 |
SM-82
|
29
| Breast | HBOC |
TP53
| c.1010G > A; p.R337H | Missense | 10 | IARC TP53 |
Variant | No. of families carrying VUS | Co-occurrence with pathogenic mutation | Gene | BIC | In silico analysis | IARC-LOVD database | ||
---|---|---|---|---|---|---|---|---|
Polyphen-2 | SIFT | Align GVGD | ||||||
p.I1237M | 1 | No |
BRCA1
| Unknown | Benign | Tolerated | C0 | - |
p.S1448G | 1 | No |
BRCA1
| Unknown | Benign | Affect | C0 | - |
p.A1615T | 1 | No |
BRCA1
| Unknown | Possibly | Affect | C0 | - |
p.M1783T | 1 | No |
BRCA1
| Unknown | Probably | Affect | C55 | - |
p.K322Q | 1 | No |
BRCA2
| Unknown | Benign | Affect | C0 | - |
p.L366V | 1 | No |
BRCA2
| Novel | Benign | Tolerated | C0 | - |
p.A495T | 1 | No |
BRCA2
| Novel | Benign | Tolerated | C0 | - |
p.M784V | 4 | No |
BRCA2
| Unknown | Benign | Tolerated | C0 | Class 3 |
p.K1533N | 1 | No |
BRCA2
| Unknown | Benign | Tolerated | C0 | - |
p.H1561N | 1 | Yes |
BRCA2
| Unknown | Benign | Tolerated | C0 | - |
p.M1915T | 3 | No |
BRCA2
| Unknown | Benign | Tolerated | C0 | - |
p.G2044V | 1 | Yes |
BRCA2
| Unknown | Benign | Tolerated | C0 | - |
p.V2138F | 2 | Yes |
BRCA2
| Unknown | Benign | Tolerated | C0 | - |
p.I2490T | 3 | Yes |
BRCA2
| Unknown | Benign | Tolerated | C45 | - |
p.I2944F | 2 | Yes |
BRCA2
| Unknown | Probably | Affect | C0 | - |
p.A3029T | 1 | No |
BRCA2
| Unknown | Benign | Tolerated | C0 | - |
p.I3412V | 1 | Yes |
BRCA2
| Unknown | Benign | Tolerated | C0 |
Mutation frequency by inclusion criteria
Hereditary Breast and Ovarian Cancer (HBOC) | Distribution by criterion | Number of mutation carriers | Positive detection rate |
---|---|---|---|
1. BC ≤ 45 years of age (no family history) | 11 | 0 | 0% |
2. BC ≤ 45 years of age with ≥ 1 relative with BC, OC, FTC and PPC at any age | 42 | 14 | 33% |
3. BC < 45 ≤ 50 years of age with ≥ 1 relative with BC, OC, FTC and PPC ≤ 50 years of age | 16 | 2 | 12% |
4. BC >50 years of age with ≥ 1 relatives with BC, OC, FTC and PPC at any age | 28 | 5 | 18% |
5. Two BC when the first occurrence was prior to age 50 | 5 | 1 | 20% |
6. BC at any age plus OC, FTC and PPC at any age | 9 | 4 | 44% |
7. Ashkenazi Jewish ancestry | 5 | 4 | 80% |
8. OC, FTC and PPC at any age | 3 | 1 | 33% |
9. Male BC | 1 | 0 | 0% |