Letter-writing is an integral practice for genetic health professionals. In Victoria, Australia, patients with a chromosomal variant of uncertain clinical significance (VUS) referred to a clinical geneticist (CG) for evaluation receive consultation summary letters. While communication of uncertainty has been explored in research to some extent, little has focused on how uncertainty is communicated within consultation letters. We aimed to develop a multi-layered understanding of the ways in which CGs communicate diagnostic uncertainty in consultation summary letters. We used theme-oriented discourse analysis of 49 consultation summary letters and thematic analysis of a focus group involving eight CGs. Results showed that CGs have become more confident in their description of VUS as 'contributing factors' to patients' clinical features, but remain hesitant to assign definitive causality. CGs displayed strong epistemic stance when discussing future technological improvements to provide hope and minimise potentially disappointing outcomes for patients and families. CGs reported feeling overwhelmed by their workload associated with increasing numbers of patients with VUS, and this has led to a reduction in the number of review appointments offered over time. This study provides a rich description of the content and process of summary letters discussing VUS. Our findings have implications for letter-writing and workforce management. Furthermore, these findings may be of relevance to VUS identified by genomic sequencing in clinical practice. European Journal of Human Genetics (2017) 25, 22-30; doi:10.1038/ejhg.2016.135; published online 16 November 2016 INTRODUCTIONChromosomal microarray (CMA) is currently recommended as a firsttier diagnostic test for children with global developmental delay, intellectual disability and autism spectrum disorder. 1 The higher resolution of CMA in detecting copy number variations (CNVs) has resulted in a 15-20% diagnostic yield compared to 3% with conventional karyotyping in this patient cohort. 1 Additionally, CMA has resulted in a greater detection of chromosomal variants of uncertain clinical significance (VUS). 2,3 Although VUS are enriched in patient cohorts, they are also identified in apparently healthy control populations, and therefore their clinical significance is uncertain.The Victorian Clinical Genetics Services (VCGS) in Melbourne, Australia began using CMAs diagnostically in 2009 and has reported approximately 37 000 CMA results, including approximately 1500 VUS at the time of this study. Two recurrent microdeletions consistently reported at the time by the VCGS laboratory as VUS involve chromosome regions 15q11.2 (containing the NIPA1 and NIPA2 genes) and 16p13.11 (containing the NDE1 gene). These microdeletions can be inherited or arise de novo. They are incompletely penetrant, and phenotypic expressivity is often highly variable even within families. 4,5 Patients in whom a VUS is detected by CMA are seen by a clinical geneticist (CG) for clinical evaluation and genetic...