Specifications of the ACMG/AMP Variant Classification Guidelines for Germline DICER1 Variant Curation
Table 5
Classification of 40 germline DICER1 variants during the pilot phase of the DICER1-specific ACMG/AMP variant curation guidelines. Round 1 and round 2 criteria reflect criteria from the preliminary and finalized guidelines, respectively.
DICER1 variant
ClinVar ID
ClinVar classifications†
Round 1 criteria applied‡
Initial classification
Round 2 criteria added‡
Points
Final classification§
c.4748T>G (p.L1583R)
4468
P/LP
PM2_P, PP3, PS3_P, PS4_P, PP1
VUS
PP1 ⟶ PP1_M
6
LP
c.5125G>A (p.D1709N)
690480
P
PM2_P, PP3, PM1, PS3_P, PS4_M, PS2_VS
P
15
P
c.5441C>T (p.S1814L)
412119
P/LP
PM2_P, PP3, PM1_P, PS3_P, PS4, PP4, PP1_S
P
13
P
c.5465A>T (p.D1822V)
254350
P/LP
PM2_P, PP3, PM1_P, PS3_P, PS4_M
LP
6
LP
c.5138A>T (p.D1713V)
690454
P/LP
PM2_P, PP3, PM1, PS3_P, PS2_P
LP
6
LP
c.5104C>T (p.Q1702)
254344
P
PM2_P, PVS1, PS4_P
P
10
P
c.1408G>T (p.E470)
254287
P
PM2_P, PVS1, PS4_P, PP4
P
11
P
c.3019C>T (p.Q1007)
429113
P
PM2_P, PVS1, PS4_P, PP4
P
11
P
c.1880_1883del (p.I627fs)
254298
P
PM2_P, PVS1, PS4_P, PP1
P
11
P
c.878_881del (p.R293fs)
254355
P
PM2_P, PVS1, PS4_P, PP4
P
11
P
c.2650+1G>T
254310
P
PM2_P, PVS1, PS4_M
P
11
P
c.1907+1G>A
429148
P/LP
PM2_P, PVS1, PS4_P, PM6
P
12
P
c.2988−1G>T
429116
P
PM2_P, PVS1, PS4_M, PS2
P
15
P
c.5479del (p.1827fs)
477261
P/LP
PVS1, PM2_P, PS4_P
P
10
P
c.2614G>A (p.A872T)
133967
B/LB
BS1, BP4, BS3_P
LB
BS2
-10
B
c.4910C>T (p.S1637L)
242127
B/LB
BS1, BP4
LB
BS2
-9
B
c.3828T>A (p.D1276E)
794388
LB
BS1, BP4
LB
-5
LB
c.3428T>C (p.L1143P)
220594
B/LB
BS1, BP4
LB
BS2
-9
B
c.1825G>T (p.D609Y)
133965
B/LB
BA1 (BS1, BP4)
B
BS2
NA
B
c.884C>G (p.S295C)
242151
B/LB
BA1 (BP4)
B
BS2
NA
B
c.59C>T (p.A20V)
133964
B/LB
BS1, BP4
LB
BS2
-9
B
c.5052C>G (p.L1684=)
242128
LB
BS1, BP4, BP7
LB
-6
LB
c.2808T>C (p.Y936=)
751425
LB
BP4, BP7
LB
-4
LB
c.4647C>T (p.H1549=)
417113
B/LB
BP4, BP7
LB
BS2
-6
LB
c.5521C>T (p.L1841=)
477262
LB
PM2_P, BP4, BP7
LB
-1
LB
c.3269+14G>A
315107
B/LB
BP4, BP7
LB
BS2
-6
LB
c.5096−12G>A
580203
VUS
PS3, PS4_M, PP4, PM2_P
LP
8
LP
c.1722_1724del (p.E574del)
566588
VUS
PM2_P, PM4_P
VUS
2
VUS
c.2651−4T>G
543697
Conflicting: LB(1); VUS(1)
BP4, BP7
LB
-2
LB
c.238G>T (p.E80)
649946
Conflicting: P(1); VUS(1)
PVS1, PM2_P
LP
9
LP
c.5276A>G (p.K1759R)
133974
Conflicting: LB(1); VUS(1)
BP4, PM1_P
VUS
BS2
-4
LB
c.5107C>T (p.R1703C)
242130
VUS
PP3, PM1_P, PM2_P
VUS
3
VUS
c.4178_4180dup (p.N1393dup)
242100
VUS
PM4_P
VUS
BS2_P
0
VUS
c.5G>A
315099
Conflicting: LB(1); VUS(2)
BP4
VUS
BS2_P
-2
LB
c.5563C>T (p.R1855)
947388
VUS
PVS1_M, PM2_P
VUS
3
VUS
c.4024C>T (p.R1342C)
412120
VUS
PM2_P
VUS
1
VUS
c.1907+3A>T
820285
Conflicting: LB(1); VUS(1)
PM2_P; BS3
VUS
Points
-3
LB
c.2T>C (p.M1T)
242076
VUS
PM4_P
VUS
1
VUS
c.5422A>G (p.M1808V)
477260
VUS
PM1_P
VUS
1
VUS
c.2642T>C (p.L881P)
690445
VUS
PP3, PP4, PM2_P, PS3_P, PS4_P
VUS
PP1, points
6
LP
†ClinVar classifications were pulled in November 2020 with the exception of p.D1713V and p.Leu1827fs due to a known incongruence between one laboratory’s ClinVar submissions (VUS) and internal classifications (LP) at the time of the data pull. ‡Modified strength levels are denoted with an underscore followed by a P, M, S, or VS, denoting supporting, moderate, strong, or very strong strength. §Classifications that changed between round 1 and round 2 are in bold text.
