对于与功能丧失变异相关的疾病风险的可靠估计的基因,病例对照数据可用于估计定义的变体组的典型风险效应的变体比例,与变体分类相关。从病例对照数据中得出典型致病变异比例的最大似然估计,并将其应用于ATM的罕见变异计数。BARD1,BRCA1,BRCA2,CHEK2,PALB2,RAD51C,和RAD51D来自已发表的乳腺癌研究:BEACCON(5770个家族病例和5741个对照)和诊断测序后的乳腺癌风险(60,466个家族和人群病例和53,461个对照)。在罕见的非编码变异中有致病性变异的重要证据,特别是更深的内含子变体,对于BRCA1(13%,p=8.3×10-7),BRCA2(6%,p=0.016)和PALB2(13%,p=0.001)。致病性错义变异的估计比例在基因之间明显不同,通常在家族病例中富集,例如,BRCA2为9%,CHEK2为60%-90%。按位置分层错义变体表明,对于大多数基因来说,功能域内的位置显着预测致病性,而域外的位置提供了针对致病性的有力证据。我们的方法为特定乳腺癌基因的致病变异谱提供了新的见解,并具有更广泛的应用,以告知美国医学遗传学和基因组学学院(ACMG)/分子病理学协会(AMP)编码的基因聚焦规范。
For genes with reliable estimates of disease risk associated with loss-of-function variants,
case-control data can be used to estimate the proportion of variants of typical risk effect for defined groups of variants, of relevance for variant classification. A calculation was derived for a maximum likelihood estimate of the proportion of pathogenic variants of typical effect from
case-control data and applied to rare variant counts for ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, and RAD51D from published breast cancer studies: BEACCON (5770 familial cases and 5741 controls) and breast cancer risk after diagnostic sequencing (60,466 familial and population-based cases and 53,461 controls). There was significant evidence of pathogenic variants among rare noncoding variants, in particular deeper intronic variants, for BRCA1 (13%, p = 8.3 × 10-7 ), BRCA2 (6%, p = 0.016) and PALB2 (13%, p = 0.001). The estimated proportion of pathogenic missense variants varied markedly between genes, generally with enrichment in familial cases, for example, 9% for BRCA2 versus 60%-90% for CHEK2. Stratifying missense variants by position indicated that, for most genes, location within a functional domain significantly predicted pathogenicity, whereas location outside domains provided robust evidence against pathogenicity. Our approach provides novel insights into the spectrum of pathogenic variants of specific breast cancer genes and has wider application to inform gene-focused specifications of American College of Medical Genetics and Genomics (ACMG)/Association of Molecular Pathology (AMP) codes for variant curation.