Whole genome sequencing in clinical practice.

Whole genome sequencing (WGS) is becoming the preferred method for molecular genetic diagnosis of rare and unknown diseases and for identification of actionable cancer drivers. Compared to other molecular genetic methods, WGS captures most genomic variation and eliminates the need for sequential genetic testing. Whereas, the laboratory requirements are similar to conventional molecular genetics, the amount of data is large and WGS requires a comprehensive computational and storage infrastructure in order to facilitate data processing within a clinically relevant timeframe. The output of a single WGS analyses is roughly 5 MIO variants and data interpretation involves specialized staff collaborating with the clinical specialists in order to provide standard of care reports. Although the field is continuously refining the standards for variant classification, there are still unresolved issues associated with the clinical application. The review provides an overview of WGS in clinical practice - describing the technology and current applications as well as challenges connected with data processing, interpretation and clinical reporting.

Germline RET Leu56Met Variant Is Likely Not Causative of Multiple Endocrine Neoplasia Type 2.

Activating variants in the receptor tyrosine kinase REarranged during Transfection (RET) cause multiple endocrine neoplasia type 2 (MEN 2), an autosomal dominantly inherited cancer-susceptibility syndrome. The variant c.166C>A, p.Leu56Met in RET was recently reported in two patients with medullary thyroid cancer (MTC). The presence of a pheochromocytoma in one of the patients, suggested a possible pathogenic role of the variant in MEN 2A. Here, we present clinical follow up of a Danish RET Leu56Met cohort. Patients were evaluated for signs of MEN 2 according to a set of predefined criteria. None of the seven patients in our cohort exhibited evidence of MEN 2. Furthermore, we found the Leu56Met variant in our in-house diagnostic cohort with an allele frequency of 0.59%, suggesting that it is a common variant in the population. Additionally, none of the patients who harbored the allele were listed in the Danish MTC and MEN 2 registries. In conclusion, our findings do not support a pathogenic role of the Leu56Met variant in MEN 2.