BCL2

Overview

BCL2 mutations are frequently found in DLBCL, particularly in the germinal center B-cell (GCB) subtype, and are often located in the flexible loop domain and outside the BCL2-homology domains. These mutations are caused by the somatic hypermutation process.¹ The presence of these mutations are strongly correlated with the presence of a translocation between BCL2 and one of the immunoglobulin loci. ² Although missense mutations may not be under positive selective pressure in the context of lymphomagenesis, some of these mutations may interfere with the function of BCL2 antagonists.³

Relevance tier by entity

Entity	Tier	Description
	1-a	high-confidence DLBCL gene, hypermutated
	1-a	high-confidence FL gene, hypermutated
	2	relevance in PMBL/cHL/GZL not firmly established
	2	relevance in BL not firmly established

Mutation incidence in large patient cohorts (GAMBL reanalysis)

Entity	source	frequency (%)
BL	GAMBL genomes+capture	0.46
BL	Thomas cohort	0.00
BL	Panea cohort	1.00
DLBCL	GAMBL genomes	23.71
DLBCL	Schmitz cohort	10.60
DLBCL	Reddy cohort	12.90
DLBCL	Chapuy cohort	15.80
FL	GAMBL genomes	50.35

Mutation pattern and selective pressure estimates

Entity	aSHM	Significant selection	dN/dS (missense)	dN/dS (nonsense)
BL	Yes	No	0.000	0
DLBCL	Yes	Yes	2.645	0
FL	Yes	No	1.197	0

aSHM regions

chr_name	hg19_start	hg19_end	region	regulatory_comment
chr18	60796984	60814103	intron	strong_enhancer
chr18	60982728	60988342	TSS	active_promoter

[!NOTE] First described in FL in 2011 by Morin RD

## BCL2 Hotspots

Chromosome	Coordinate (hg19)	ref>alt	HGVSp
chr18	60985854	T>C	M16V
chr18	60985854	T>A	M16L
chr18	60985853	A>T	M16K
chr18	60985852	C>T	M16I
chr18	60985849	C>G	K17N
chr18	60985842	G>A	H20Y
chr18	60985840	A>C	H20Q
chr18	60985838	T>G	Y21S
chr18	60985835	T>C	K22R
chr18	60985834	CT>TC	K22R

View coding variants in ProteinPaint hg19 or hg38

View all variants in GenomePaint hg19 or hg38

References

1. Schuetz JM, Johnson NA, Morin RD, Scott DW, Tan K, Ben-Nierah S, Boyle M, Slack GW, Marra MA, Connors JM, Brooks-Wilson AR, Gascoyne RD. BCL2 mutations in diffuse large B-cell lymphoma. Leukemia. 2012 Jun;26(6):1383-90. doi: 10.1038/leu.2011.378. Epub 2011 Dec 22. PMID: 22189900.
2. Hilton L et al. Motive and Opportunity: MYC rearrangements in high-grade B-cell lymphoma with MYC and BCL2 rearrangements-an LLMPP study. Blood. 2024. Epub May 3.
3. Singh K, Briggs JM. Functional Implications of the spectrum of BCL2 mutations in Lymphoma. Mutat Res Rev Mutat Res. 2016 Jul-Sep;769:1-18. doi: 10.1016/j.mrrev.2016.06.001. Epub 2016 Jun 16. PMID: 27543313. ## BCL2 Expression