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Outcomes of tumour analysis after negative blood analysis in determining mosaicism and utility in testing offspring

Adapted from Table 6.r

Examples of hits in the NF2 gene identified in tumour specimens  Is mosaicism confirmed?  Definitive test in offspring after single tumour analysis? Second tumour analysis Test in offspring for confirmed mosaic pathogenic variant in affected patient
Point pathogenic variant (A) + LOH Yes - need second Tumour* MLPA + point pathogenic variant A or testing for heterozygosity at intronic CA repeat + pathogenic variant A Point pathogenic variant (A) Only necessary to test for point pathogenic variant A
Point pathogenic variant (A) + LOH + MLPA normal Yes - confirms mitotic recombination Only necessary to test for point pathogenic variant A  Not required Only necessary to test for point pathogenic variant A
Point pathogenic variant A + point pathogenic variant B Yes - need second tumour* - ensure at full dosage as could be multifocal Test offspring for both point pathogenic variant A and point pathogenic variant B Point pathogenic variant A + LOH Only necessary to test for point pathogenic variant A
Point pathogenic variant A, no second hit, no LOH No - need second Tumour* No definitive test to exclude NF2 Point pathogenic variant A Only necessary to test for point pathogenic variant A

Point pathogenic variant A, no second hit, no LOH

 No - need second Tumour* No definitive test to exclude NF2 Point pathogenic variant A not present no LOH No definitive test to exclude NF2

Point pathogenic variant A, no second hit, no LOH

 No - need second Tumour* No definitive test to exclude NF2 Point pathogenic variant A not present, but LOH Test for inheritance of lost allele: patient mosaic for pathogenic variant on retained allele
Point pathogenic variant A + MLPA whole gene deletion and LOH Yes - need second Tumour* MLPA + point pathogenic variant A No point pathogenic variant A, but MLPA + LOH MLPA-patient mosaic for whole gene deletion
Point pathogenic variant A + MLPA exons 1-4 deletion and LOH for intragenic marker only for intrage Yes - need second Tumour* MLPA + point pathogenic variant A No point pathogenic variant A, but MLPA 1-4 MLPA-patient mosaic for exons 1-4 deletion
No point pathogenic variant, but LOH No - need second Tumour* Test for inheritance of lost allele and MLPA, patient mosaic for pathogenic variant on retained allele   Patient may be mosaic for MLPA detectable deletion or a point pathogenic variant on the retained allele
Nil identified No - need second Tumour* No test available Point pathogenic variant A No test available
Nil identified No - need second Tumour* No test available Point pathogenic variant A + LOH MLPA + point pathogenic variant A: first tumour may have been contaminated with normal material and patient mosaic for point pathogenic variant or deletion

LOH, loss of heterozygosity; MLPA, multiple ligation dependant probe amplification; NF2, neurofibromatosis type 2.

*Need second tumour to confirm which abnormality the patient is mosaic for. In practice, most individuals will be mosaic for the point pathogenic variant, if this is identified with LOH; this is extremely likely if LOH extends substantially beyond the NF2 gene. Point pathogenic variant plus mitotic recombination which can be inferred if MLPA shows no dosage loss will confirm the point pathogenic variant as the underlying mosaic pathogenic variant. When LOH is present there is a 50% chance of excluding NF2 in the offspring if the child can be shown to have inherited the allele lost in the tumour. If this allele is the second hit (the usual situation) then it is the wild-type allele. If it is a mosaic loss of the intragenic marker then inheritance of the marker excludes inheritance of the deletion.

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Version 3

Date Summary of changes
31/05/2017

Transferred to new eviQ website. Version change to V.2. 

Previous website ID: 360
20/09/2018 Presented at May 2018 RCM and discussion continued over email. Approved to publish with nil changes.
06/09/2019 "Mutation" changed to "pathogenic variant" throughout document for consistency among eviQ cancer genetics protocols per agreement among the cancer genetics reference committees' chairs. Definition of "pathogenic variant" added as a pop-up. Version number increased to V.3.

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https://www.eviq.org.au/p/3191

01 Mar 2021