Our genomes influence nearly every aspect of human biology—from molecular and cellular
functions to phenotypes in health and disease. Studying the differences in DNA sequence …

Genetic abnormalities in the DNA repair genes BRCA1 and BRCA2 predispose to hereditary
breast and ovarian cancer (HBOC). However, only approximately 25% of cases of HBOC …

Personalized genome sequencing has revealed millions of genetic differences between
individuals, but our understanding of their clinical relevance remains largely incomplete. To …

Variants of uncertain significance fundamentally limit the clinical utility of genetic information.
The challenge they pose is epitomized by BRCA1, a tumour suppressor gene in which …

The genetic dependencies of human cancers widely vary. Here, we catalog this
heterogeneity and use it to identify functional gene interactions and genotype-dependent …

Many high-throughput experimental technologies have been developed to assess the
effects of large numbers of mutations (variation) on phenotypes. However, designing …

The assessment of variant effect predictor (VEP) performance is fraught with biases
introduced by benchmarking against clinical observations. In this study, building on our …

Determining the pathogenicity of genetic variants is a critical challenge, and functional
assessment is often the only option. Experimentally characterizing millions of possible …

The functions of proteins and RNAs are defined by the collective interactions of many
residues, and yet most statistical models of biological sequences consider sites nearly …

Classical genetic approaches for interpreting variants, such as case-control or co-
segregation studies, require finding many individuals with each variant. Because the …