Gene affected:
Baculoviral IAP repeat-containing protein3 (BIRC3, also known as cIAP2)

Clinical significance
Inactivating mutations of BIRC3 are associated with more rapidly progressive disease or treatment resistance in CLL or MCL (affecting fludarabine or ibrutinib therapy). Detecting BIRC3 mutation may therefore inform treatment choice in these disorders, although this has not entered treatment guidelines.

Function of gene

In the resting cells, BIRC3 (and its homologue BIRC2) oppose activation of the NF-κB signalling pathway. Absent or dysfunctional BIRC2/3 (caused by mutation) therefore may augment NF-κB signalling and may bypass some inhibitory actions of ibrutinib. Monoallelic lesions are frequent in haematological disease, suggesting BIRC3 mutation may have a dominant negative effect.

NGS panel gene coverage

The panel covers the whole gene. (Chr 11q22.2)

Occurrence and significance

Involvement in chromosomal translocations
Although not a direct mutation, BIRC3 may be deleted as part of chromosomal lesions involving 11q in CLL, and is inactivated in the t(11;18)(q21;q21) (forming part of the inactive BIRC3/MALT1 fusion protein) in marginal zone lymphomas
Loss of function mutations in 2-4% of chemo naive, early stage CLL patients
Mantle cell lymphoma
Occurs in 6-10% of cases (small series)
Splenic marginal zone lymphoma
Occurs in 11% of cases (small series)


GeneWiki link:
Gene Wiki entry for BIRC3
General references