Variants of uncertain clinical significance in hereditary breast and ovarian cancer genes: best practices in functional analysis for clinical annotation
Germline DNA tests to identify pathogenic variants in genes linked to hereditary breast and ovarian cancer susceptibility have become widely available. However, the clinical utility of genetic testing depends on reliable evidence-based classification of sequence variants. Determination of pathogenicity traditionally relies on painstaking pedigree-based segregation analyses. However, the rapid increase in usage of germline DNA tests has led to the discovery of a large number of variants of uncertain clinical significance (VUS). For most VUS there is insufficient information for segregation analysis and therefore assessment of functional consequences is increasingly being used to support clinical annotation. Functional assays need to be accurate, robust, and reproducible to be used for clinical purposes. Here we use the lessons learned from
Journal
Journal of Medical GeneticsFunding
Analysis of BRCA1 recombination functionsBRCA2 missense mutations and breast cancerBIOKE FundingIDT FundingNetherlands Organization for Scientific Research FundingRoyal Netherlands Academy of Arts and Sciences FundingDanish Counsil for Independent Research FundingNetherlands Cancer Institute Funding