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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).