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Efforts are ongoing to determine the significance of unclassified variants (UVs) in the breast cancer susceptibility genes  BRCA1 / BRCA2 , but no study has systematically assessed whether women carrying the suspected deleterious UVs have characteristics commonly seen among women carrying known deleterious or disease-causing mutations in  BRCA1 / BRCA2 .    Methods  We sequenced  BRCA1 / BRCA2  in 1,469 population-based female breast cancer patients diagnosed between the ages of 20 and 49 years. We used existing literature to classify variants into known deleterious mutations, polymorphic variants, and UVs. The UVs were further classified as high risk or low risk based on five methods: allele frequency, Polyphen algorithm, sequence conservation, Grantham matrix scores, and a combination of the Grantham matrix score and sequence conservation. Furthermore, we examined whether patients who carry the variants classified as high risk using these methods have risk characteristics similar to patients with known deleterious  BRCA1 / BRCA2  mutations (early age at diagnosis, family history of breast cancer or ovarian cancer, and negative estrogen receptor/progesterone receptor).    Results  We identified 262 distinct  BRCA1 / BRCA2  variants, including 147 UVs, in our study population. The  BRCA1  UV carriers, but not the  BRCA2  UV carriers, who were classified as high risk using each classification method were more similar to the deleterious mutation carriers with respect to family history than those carriers classified as low risk. For example, the odds ratio of having a first-degree family history for the high-risk women classified using Polyphen was 3.39 (95% confidence interval = 1.16 to 9.94) compared with normal/polymorphic  BRCA1  carriers. The corresponding odds ratio of low-risk women was 1.53 (95% confidence interval = 1.07 to 2.18). The odds ratio for high-risk women defined by allele frequency was 2.00 (95% confidence interval = 1.14 to 3.51), and that of low-risk women was 1.30 (95% confidence interval = 0.87 to 1.93).    Conclusion  The results suggest that the five classification methods yielded similar results. Polyphen was particularly better at isolating  BRCA1  UV carriers likely to have a family history of breast cancer or ovarian cancer, and may therefore help to classify  BRCA1  UVs. Our study suggests that these methods may not be as successful in classifying  BRCA2  UVs.

breast cancer research

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