Approach to genetic testing for NF2/SWN in the patient who does not meet clinical criteria

NF2: NF2-related schwannomatosis; SWN: schwannomatosis; NF2: NF2, moesin-ezrin-radixin like (MERLIN) tumor suppressor; SMARCB1: SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily b, member 1; LZTR1: leucine zipper like transcription regulator 1; VUS: variant of unknown significance; SMARCE1: SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily e, member 1; SUFU: SUFU negative regulator of hedgehog signaling.

* Given the occurrence of known isolated vestibular schwannomas in the aging population, individuals over 30 years of age with no other manifestations of NF2 may not warrant genetic testing.

¶ Mosaic cases of NF2 and SWN are well documented. Typically, testing begins with blood and may require other affected tissues (eg, two independent tumors) to identify a common variant and to distinguish between a germline and a somatic variant. It is important to note that individuals with previously normal genetic testing may be mosaic and one should confirm testing was done using the latest technology and include affected tissue whenever possible.

Δ In cases where tumor/tissue testing is indicated, paraffin-embedded specimens may not be accepted. Consult the testing laboratory for specifics regarding sample requirements.

◊ NF2 is frequently included on multigene somatic tumor panels, as it is a known molecular driver of tumor formation, including isolated schwannomas, meningiomas, and ependymomas. In these cases, discovery of an NF2 or SWN pathogenic variant may not be indicative of a germline/constitutional variant. Further testing of blood or alternative tissue and evaluation by an NF2/SWN specialist may be indicated. Meningiomas have also been associated with SMARCE1 and SUFU pathogenic variants. Additional testing of these genes may be considered.

§ Literature exists in support of NF2 genetic testing for individuals with one or more features of NF2 who do not meet clinical diagnostic criteria, such as individuals with NF2-associated ocular findings and solitary ependymoma.

¥ Whenever possible, genetic testing should be done on a known affected individual. If a pathogenic variant is identified, known familial variant testing can be done, and if negative, no additional evaluation is needed.