ClinVar

This variant, formerly designated HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 2, with the 'included' title of LYMPHOMA, NON-HODGKIN, has been reclassified based on the report by Clementi et al. (2005).

In a patient with familial hemophagocytic lymphohistiocytosis (FHL2; 603553), Stepp et al. (1999) identified a 755A-G transition in the PRF1 gene, resulting in an asn252-to-ser (N252S) substitution.

In a 27-year-old man with autoimmune lymphoproliferative syndrome (601859) who later developed a T-cell-rich, histiocyte-rich, diffuse large B-cell lymphoma (605027), Clementi et al. (2004) identified a heterozygous N252S mutation in the PRF1 gene and a heterozygous mutation in the FAS gene (134637). The FAS mutation was inherited from his healthy father and was also carried by his healthy brother, whereas the PRF1 mutation was inherited from his healthy mother. Clementi et al. (2004) noted that the N252S substitution occurs within the membrane attack complex of the perforin protein, a region involved in the pore-forming activity of the molecule. However, both the patient and his mother had normal levels of perforin and normal NK cell activity. The authors suggested that the combined effect of the 2 mutant genes contributed to the development of ALPS and lymphoma in this patient. Rieux-Laucat et al. (2005) cast doubt on the pathogenicity of the N252S mutation, and the primary authors provided a rebuttal (Clementi et al., 2005).

Clementi et al. (2005) identified the N252S mutation in 1 of 660 (0.02%) control alleles, suggesting that it is a benign polymorphism.