Multigene testing of moderate-risk genes: be mindful of the missense

What fraction of early-onset breast cancer patients inherited a clinically actionable moderate-risk genotype? To estimate this, we applied both multi-gene mutation screening and SNP genotyping to 1,297 early onset breast cancer cases and 1,121 controls. Mutation screening revealed that 2.1% of the cases carried an obviously pathogenic protein-truncating variant in one of nine moderate-risk genes, plus 5.4% carried a missense substitution with a high-probability of pathogenicity. In addition, 2.1% carried a notable excess of individually modest-risk SNPs. Thus, beyond mutations in high-risk genes such as BRCA1 and BRCA2, a further 9.6% of early onset cases inherited an actionable moderate-risk genotype. (By Erin Young, http://jmg.bmj.com/content/early/2016/01/19/jmedgenet-2015-103398 )