Women's College Research Institute, University of Toronto, Toronto, ON, Canada.
J Med Genet. 2011 Nov;48(11):783-6. doi: 10.1136/jmedgenet-2011-100305. Epub 2011 Oct 1.
Women who carry a pathogenic mutation in BRCA1 or BRCA2 have high risks of developing breast and ovarian cancers. The functional effect of many missense variants on BRCA1 and BRCA2 protein function is not known. Here, the authors construct a historical cohort of 4030 female first-degree relatives of 1345 unselected patients with ovarian cancer who have been screened for BRCA1 and BRCA2 mutations. The authors compared the risks by the age of 80 years for all cancers combined in female first-degree relatives of women with a pathogenic mutation, women with a variant of unknown significance (unclassified variant) and non-carriers. The cumulative risk of cancer among the relatives of patients with a pathogenic mutation was much higher than the risk in relatives of non-carriers (50.2% vs 28.5%; HR=2.87, p<10(-4)). In contrast, the cumulative risk of cancer among relatives of patients carrying an unclassified variant was similar to the risk of cancer for relatives of non-carriers (27.6% vs 28.5%; HR=1.08, p=0.79). The authors used three different algorithms to predict the pathogenicity of unclassified variants and compared their penetrance with non-carriers. In this sample, only Align Grantham Variation Grantham Deviation appeared to predict penetrance based on first-degree relatives.
携带 BRCA1 或 BRCA2 致病性突变的女性罹患乳腺癌和卵巢癌的风险较高。许多错义变体对 BRCA1 和 BRCA2 蛋白功能的功能影响尚不清楚。在这里，作者构建了一个由 4030 名女性组成的历史队列，这些女性是 1345 名未经选择的卵巢癌患者的一级亲属，这些患者已经接受了 BRCA1 和 BRCA2 突变筛查。作者比较了携带致病性突变、具有未知意义的变异（未分类变异）和非携带者的女性一级亲属中所有癌症的 80 岁时的风险。携带致病性突变的患者亲属的癌症累积风险远高于非携带者的风险（50.2% vs 28.5%；HR=2.87，p<10(-4)）。相比之下，携带未分类变异的患者亲属的癌症累积风险与非携带者的癌症风险相似（27.6% vs 28.5%；HR=1.08，p=0.79）。作者使用了三种不同的算法来预测未分类变体的致病性，并将其外显率与非携带者进行了比较。在这个样本中，只有 Align Grantham Variation Grantham Deviation 似乎可以根据一级亲属来预测外显率。
