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Table 3 Association between family history of breast cancer or ovarian cancer and BRCA1 or BRCA2 status of the breast cancer patients

From: Evaluation of unclassified variants in the breast cancer susceptibility genes BRCA1 and BRCA2using five methods: results from a population-based study of young breast cancer patients

Mutation/unclassified variant status

None

First degree

Second degree

 

n a

n a

OR (95% CI)b

P valuec

n a

OR (95% CI)b

P valuec

BRCA1 d

Normal/polymorphism (reference)

600

166

1

 

282

1

 

Definitely disease-causing variant

13

35

11.3 (5.73 to 22.5)

<0.001

11

1.89 (0.83 to 4.31)

0.13

Unclassified variant

156

67

1.54 (1.10 to 2.15)

0.012

75

1.02 (0.74 to 1.39)

0.90

Unclassified variant classification using

Allele frequency

   High risk (LFUV)

39

21

2.00 (1.14 to 3.51)

0.016

22

1.20 (0.70 to 2.06)

0.52

   Low risk (HFUV)

115

42

1.30 (0.87 to 1.93)

0.20

52

0.96 (0.67 to 1.37)

0.82

Polyphene

   Probably damaging missense

7

7

3.39 (1.16 to 9.94)

0.026

6

1.80 (0.60 to 5.40)

0.30

   Possibly damaging missense

9

1

0.44 (0.06 to 3.54)

0.44

5

1.19 (0.40 to 3.60)

0.75

   Benign missense

133

57

1.53 (1.07 to 2.18)

0.021

61

0.97 (0.70 to 1.36)

0.87

Sequence conservatione

   High or moderatef

50

23

1.68 (0.99 to 2.85)

0.053

32

1.35 (0.85 to 2.16)

0.20

   High

6

3

1.88 (0.46 to 7.63)

0.38

8

2.85 (0.98 to 8.30)

0.055

   Moderate

44

20

1.66 (0.95 to 2.91)

0.076

23

1.10 (0.65 to 1.86)

0.72

   Low

99

40

1.43 (0.95 to 2.16)

0.085

41

0.88 (0.60 to 1.31)

0.53

Grantham matrix scoree

   High (>60)

15

10

2.38 (1.04 to 5.45)

0.039

10

1.42 (0.63 to 3.20)

0.40

   Low (≤ 60)

134

55

1.46 (1.02 to 2.10)

0.039

63

1.00 (0.72 to 1.39)

0.98

Grantham matrix score/sequence conservatione

   Deleterious

4

2

1.74 (0.32 to 9.64)

0.52

3

1.63 (0.36 to 7.33)

0.53

   Intermediate (unclassified)

46

22

1.75 (1.02 to 3.01)

0.043

25

1.15 (0.69 to 1.91)

0.60

   Neutral

99

40

1.44 (0.95 to 2.16)

0.083

44

0.95 (0.65 to 1.39)

0.78

BRCA2 g

Normal/polymorphism (reference)

279

87

1

 

137

1

 

Definitely disease-causing variant

11

13

3.69 (1.57 to 8.68)

0.003

10

1.83 (0.76 to 4.42)

0.18

Unclassified variant

462

162

1.07 (0.79 to 1.46)

0.66

213

0.93 (0.72 to 1.21)

0.59

Unclassified variant classification using

Allele frequency

   High risk (LFUV)

71

18

0.81 (0.45 to 1.45)

0.48

40

1.15 (0.74 to 1.78)

0.54

   Low risk (HFUV)

385

138

1.09 (0.79 to 1.50)

0.59

168

0.88 (0.67 to 1.16)

0.36

Polyphene

   Probably damaging missense

32

7

0.73 (0.31 to 1.74)

0.48

17

1.09 (0.58 to 2.03)

0.79

   Possibly damaging missense

108

28

0.79 (0.48 to 1.29)

0.34

42

0.78 (0.52 to 1.18)

0.24

   Benign missense

310

118

1.15 (0.83 to 1.60)

0.41

146

0.95 (0.72 to 1.26)

0.73

Sequence conservatione

   High or moderate

157

42

0.80 (0.52 to 1.23)

0.31

61

0.78 (0.55 to 1.12)

0.18

   High

96

30

0.92 (0.56 to 1.51)

0.75

41

0.86 (0.57 to 1.31)

0.48

   Moderate

61

12

0.61 (0.31 to 1.21)

0.15

20

0.66 (0.38 to 1.14)

0.13

   Low

292

113

1.18 (0.84 to 1.65)

0.33

142

0.98 (0.74 to 1.31)

0.91

Grantham matrix scoree

   High (>60)

450

155

1.05 (0.77 to 1.43)

0.76

205

0.92 (0.71 to 1.20)

0.53

   Low (≤ 60)

9

3

0.98 (0.25 to 3.85)

0.98

5

1.11 (0.37 to 3.39)

0.85

Grantham matrix score/sequence conservatione

   Deleterious

124

34

0.83 (0.52 to 1.31)

0.42

51

0.83 (0.56 to 1.22)

0.34

   Intermediate (unclassified)

66

14

0.67 (0.35 to 1.27)

0.22

28

0.87 (0.53 to 1.41)

0.56

   Neutral

259

107

1.24 (0.89 to 1.75)

0.21

124

0.97 (0.72 to 1.30)

0.82

  1. OR, odds ratio; CI, confidence interval; LFUV, low-frequency unclassified variants; HFUV, high-frequency unclassified variants. aTwenty-two and 55 women with unknown BRCA1 and BRCA2 status were included as a separate category for corresponding analyses. Numbers do not add up when further classifying unclassified variants (UVs) using the classification methods since the UV carriers who had missing values for higher-risk UV categories could not be categorized into high-risk or low-risk groups and thus were added to the unknown group. bFamily history of breast cancer or ovarian cancer is the outcome (no family history (reference), first degree, and second degree). Family history unknown cases were deleted from the analysis. All analyses were adjusted for age at diagnosis (<35 years, 35 to <40 years, 40 to <45 years, 45+ years). cBased on the chi-square test. dWhen analyzing BRCA1, the model was further adjusted for the BRCA2 mutation status (definitely disease-causing variant, non-definitely disease-causing variant, unknown). eSplice/inframe deletion carriers of BRCA1 were excluded when analyzing BRCA1. Splice/inframe deletion carriers of BRCA2 were excluded when analyzing BRCA2. fNumbers do not add up due to one additional subject classified after combining the high and moderate groups who was in the unknown BRCA1 status before combining. gWhen analyzing BRCA2, the model was further adjusted for BRCA1 mutation status (definitely disease-causing variant, non-definitely disease-causing variant, unknown).