Last year, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) updated guidance for the interpretation of sequence variants in clinical laboratories. Similarly, the market is being flooded with various interpretation tools facilitating variant filtering and interpretation based on incorporation of multiple lines of evidence into home-brewed pipelines. These developments are due to the increasing capability of whole exome and whole genome sequencing, which has outpaced ability of clinical diagnostic laboratories and physicians to interpret pathogenicity of variants of uncertain clinical significance. Therefore, while between 20 and 70% of cases undergoing whole exome sequencing may receive diagnosis, a significant proportion of them will remain unsolved. This lack of definitive molecular findings, following genetic testing, has become a major bottleneck in practicing genomics medicine; and it prevents patients from being eligible for personalized treatment and counseling.

Researchers at the session discussed the incorporation of different tools such as a “critical exon mapper” (CEM) for evaluation of copy number variants of unknown significance, and leveraging splice-affecting variant predictors to improve guidelines for the interpretation of nonsynonymous, synonymous, and intronic variants.

Scientists from Broad Institute in collaboration with Imperial College in London and Massachusetts General Hospital presented a study based on re-interpretation of 60,706 of exomes and they identified the presence of a number of false positive pathogenic variants (with allele frequency greater than 1 in 1000) in clinical variant databases. These included ancestry-specific variants, variants misclassified due to over-interpretation of functional studies, and misinterpreted variants co-occurring in cis with a pathogenic variant. Moreover, an unexpected finding was the presence of dozens of rare pathogenic variants for severe pediatric-onset dominant conditions in ExAC. Some of these were related to incomplete penetrance, and to multinucleotide polymorphisms; the others were an outcome of sequencing or alignment errors.

The Clinical Sequencing Exploratory Research (CSER) consortium presented their findings on preconception expanded carrier screening of healthy individuals utilizing whole genome sequencing (WGS). According to CSER, in a cohort of 175 participants, the bulk of novel missense variants identified in well-known genes, such as CFTR, and in genes associated with ultra-rare condition were the most problematic to be classified, and thus less likely to be reported in a carrier setting.

Overall, these findings make a compelling case for robust and reliable process in both pathogenicity assessment and its implementation in patients’ clinical management. At this moment, it is apparent that we still have a long path ahead of us when it comes to improving our practice.