Constitutional genomic variation is common, with individuals harbouring 12,000–14,000 protein-altering germline variants: the majority of which is unrelated to disease. Over the last 10 years, variant curation has become more evidence-based, objective, and systematic through the development of standardised reporting frameworks instigated by international collaborative initiatives such as ClinGen, ENIGMA and INSIGHT. The formation of international variant curation expert panels has finessed these frameworks by specifying tailored modifications for specific genes. Such approaches have reduced the number of variants classified as uncertain although rare missense variants often lack sufficient evidence to classify as benign and so remain class 3 VUSs. Research is now focussed on developing well-validated and calibrated functional assays to assess the impact of such rare missense variants on protein function. Ensuring these advances are implemented systematically across all diagnostic laboratories is a priority as clinical gene panels are ever expanding to incorporate validated genes with a spectrum of risk penetrance profiles. In parallel, the clinical oncology-based utility of identifying constitutional pathogenic variants has increased through studies such as OLYMPIAD and OLYMPIA. This has propelled implementation of germline testing towards a mainstream model with increasing numbers of patients being tested who are more likely to obtain an uncertain result due to their low prior risk of carrying a pathogenic variant. The collection of clinical information, tumour phenotype, family history, genotype is a major contributor to variant curation as it provides evidence for or against a direct link between genotype and disease. In view of this, the Parkville familial cancer centre has recently initiated a national constitutional variant reclassification forum, to foster collaboration and clinical information collection across all the familial cancer centres.