Unknown unknowns
Assigning the prevalence and cancer-causing potential of mutations in the best understood genes is beset with unknown unknowns, since only about 30% of the BRCA1 variants in reported to the ClinVar database and less than 5% of all possible single amino acid substitutions have ever been seen in the largest collection of over 120,000 whole genome sequences \cite{Karczewski_2019} assembled in the gnomAD database (2,129 BRCA1 variants of the BRCA Exchange variants are also seen in gnomAD). Gene editing allows VUS to be assigned a pathogenicity score by testing all possible substitution mutations for cell survival or cell function before they are discovered in individual people \cite{Findlay_2018}BRCA1 and four other tumor suppressor genes are essential in haploid cell lines. In those, most of 3893 BRCA1 mutations were just like known benign variants that allowed cells. In contrast, 21 known cancer-causing mutations that had no function were lethal, allowing 400 non-functional missense mutations and 300 impairing gene expression to be labeled pathogenic for the first time. Assays testing homology-directed repair of double strand DNA breaks \cite{Starita_2018} can be used to determine the activity of 6% or so mutations that showed partial loss of function in the viability assay.
Gene-environment effects
The smaller contributions of many genes throughout the genome are thought to explain population cancer risk, together with environmental factors such as hormone exposure, smoking and aging \cite{Cronin_2018}. At the population level, about 18% of the familial relative risk of breast cancer can currently be explained by mostly common variants identified by genome wide association studies \cite{Michailidou_2017}. Using these variants for polygenic prediction, the 1% of women with the highest predicted genetic risk would have a 3.5-fold (42% lifetime risk) compared to the population average (12% lifetime risk). Such tests are undergoing clinical investigation for their utility in prioritizing early detection and prevention strategies, particularly for those with sparse or unrecorded family history of cancer.