Table 2.

Potentially important germ line variants in DDR genes across hematologic malignancies

GeneDiseaseVariantFrequency (%)StudyStrength of associationCohort sizeCellular and clinical consequences
ATM CLL F858L 1.4 Rudd et al, 200616  OR, 2.28; P < .0001 992 pts; 2 707 healthy controls Attenuated p53 response to DNA damage; selective pressure for the loss of the second ATM allele through 11q deletion; earlier disease onset. 
P1054R 2.8 OR, 1.68; P = .0006 
L2307F 2.3 Tiao et al, 201717  OR, 10.1; P < .05 516 pts; 8 920 healthy controls 
2.8 Lampson et al, 202318  2.8% vs 0% (CLL vs healthy); P = .1 825 pts; 143 healthy controls 
CHEK2 CLL I157T 1 Rudd et al, 200616  OR, 14.83; P = .0008 992 pts; 2 707 healthy controls Loss of G1/S cell cycle checkpoint; earlier acquisition of JAK2 V617F mutation and younger age of onset of ET. 
ET IVS2+1G>A 2.8 Janiszewska et al, 201219  OR, 5.8; P = .02 106 pts; 200 healthy controls 
I157T 9.4 OR, 2.8; P = .04 
del5395 1.9 OR, 3.8; P = .09 
AML c.1229delC 2.0∗  Yang et al, 202220  OR, 1.21; P = .79 391 pts In silico protein modeling of CHEK2 sequence variants predicts a deleterious impact on protein function. 
I200T OR, 0.51; P = .3 
S471F Not reported 
R188W 
H186R 
R160G 
T410M 
BRCA2 CLL N372H 2.9 Rudd et al, 200616  OR, 1.45; P = .0032 992 pts; 2 707 healthy controls  
MLH3 DLBCL C40Y 5 de Miranda et al, 201321,22  5% vs 0.002% (DLBCL vs healthy); P < .01 22 pts; 60 000 healthy controls Association with MSI and genomic instability; loss of high-fidelity postreplicative DNA damage repair and protection from off-target effects of AID. 
I988M 5 5% vs 0.002% (DLBCL vs healthy); P < .01 
L111F 5 5% vs 0.0008% (DLBCL vs healthy); P < .01 
MSH3 DLBCL P657S 5 de Miranda et al, 201321,22  5% vs 0.003% (DLBCL vs healthy); P < .01 22 pts; 60 000 healthy controls 
R1061G 9 9% vs 0.02% (DLBCL vs healthy); P < .01 
GeneDiseaseVariantFrequency (%)StudyStrength of associationCohort sizeCellular and clinical consequences
ATM CLL F858L 1.4 Rudd et al, 200616  OR, 2.28; P < .0001 992 pts; 2 707 healthy controls Attenuated p53 response to DNA damage; selective pressure for the loss of the second ATM allele through 11q deletion; earlier disease onset. 
P1054R 2.8 OR, 1.68; P = .0006 
L2307F 2.3 Tiao et al, 201717  OR, 10.1; P < .05 516 pts; 8 920 healthy controls 
2.8 Lampson et al, 202318  2.8% vs 0% (CLL vs healthy); P = .1 825 pts; 143 healthy controls 
CHEK2 CLL I157T 1 Rudd et al, 200616  OR, 14.83; P = .0008 992 pts; 2 707 healthy controls Loss of G1/S cell cycle checkpoint; earlier acquisition of JAK2 V617F mutation and younger age of onset of ET. 
ET IVS2+1G>A 2.8 Janiszewska et al, 201219  OR, 5.8; P = .02 106 pts; 200 healthy controls 
I157T 9.4 OR, 2.8; P = .04 
del5395 1.9 OR, 3.8; P = .09 
AML c.1229delC 2.0∗  Yang et al, 202220  OR, 1.21; P = .79 391 pts In silico protein modeling of CHEK2 sequence variants predicts a deleterious impact on protein function. 
I200T OR, 0.51; P = .3 
S471F Not reported 
R188W 
H186R 
R160G 
T410M 
BRCA2 CLL N372H 2.9 Rudd et al, 200616  OR, 1.45; P = .0032 992 pts; 2 707 healthy controls  
MLH3 DLBCL C40Y 5 de Miranda et al, 201321,22  5% vs 0.002% (DLBCL vs healthy); P < .01 22 pts; 60 000 healthy controls Association with MSI and genomic instability; loss of high-fidelity postreplicative DNA damage repair and protection from off-target effects of AID. 
I988M 5 5% vs 0.002% (DLBCL vs healthy); P < .01 
L111F 5 5% vs 0.0008% (DLBCL vs healthy); P < .01 
MSH3 DLBCL P657S 5 de Miranda et al, 201321,22  5% vs 0.003% (DLBCL vs healthy); P < .01 22 pts; 60 000 healthy controls 
R1061G 9 9% vs 0.02% (DLBCL vs healthy); P < .01 

AID, activation-induced cytidine deaminase; ET, essential thrombocythemia; MSI, microsatellite instability; OR, odds ratio; pts, patients.

∗

Frequency shown represents that of all variants combined.

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