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Table 2 Rare RET variants: clinical feature, population database report, in silico predictive algorithms and proposition of classification following ACMG

From: Spectrum of Germline RET variants identified by targeted sequencing and associated Multiple Endocrine Neoplasia type 2 susceptibility in China

Exon Nucleotide change RET
variant
No. patient
/all carierrs
Age atdiagnosis Clinical phenotype dbSNP
(NO.)
1000 Genomes (frequenc y) ExAC (frequency) gnomAD exomes
(frequency)
SIFT PolyPhen-2
HDIV
M-CAP Oncogenic potential in vitro (Ref) Ref Classification following ACMG-2015
Single base ubstitution (missense variants)
 3 c.341G > A R114H 2/4 51.5 (50,53) MTC rs76397662 0.00139776 0.00088200 0.00076690 T B a    Likely benign
 3 c.487C > T R163W 0/1 a a a 0.00000812 D P D    UCS
 5 c.832A > G T278A 0/1 rs541929171 0.000199681 0.00001700 0.00002487 T B D   55 UCS
 5 c.833C > A T278N 2/9 53.5 (48,59) MTC rs35118262 0.00399361 0.00209900 0.00211343 D B a    UCS
 6 c.1226 C > A S409Y b 6/15 57.6 (41 ~ 75) MTC b a a a a D P D Potential (7) 7 Pathogenic
 7 c. 1441C > G L481V 1/1 39 MTC rs767210575 a 0.00003300 0.00004875 D B D    UCS
 7 c.1465G > A D489N 2/13 51 (39,63) MTC rs9282834 0.00379393 0.00207300 0.00215943 T B a   55 Benign
 8 c.1573C > T R525W 0/3 rs545625150 0.000399361 0.00002200 0.00000961 D P D Low or No (39) 32, 39 UCS
 10 c.1799G > A R600Q 1/2 41 (41) MTC rs377767393 a 0.00003300 0.00002079 T B D   52 UCS
 10 c.1810G > T A604S 2/2 45 (44,46) MTC a a a a T P D    UCS
 13 c.2363 T > G I788S 1/1 43 MTC a a a a D D D    UCS
 14 c.2465 T > A V822E 0/1 a a a a D P D    UCS
 16 c.2752A > G M918V 1/1 69 MTC rs377767442 a a a D P D Low or No (50) 15, 51,52 Pathogenic
 19 c.3052C > T L1018F 1/1 46 MTC rs766330880 a 0.00007400 0.00005686 D P D    UCS
Single base substitution (synonymous variants)
 8 c.1596C > T G532G 0/1 a a a a       Likely benign
 11 c.2037C > T P679P 2/7 47.3 (26,72) MTC rs55862116 0.00259585 0.00113000 0.00108342       Benign
 14 c.2523G > A P841P 1/3 39 MTC rs56195026 0.00059904 0.00012600 0.00009773       Likely benign
 18 c.2844G > A G948G 0/1 rs749196396 a 0.00000820 0.00000406       Likely benign
Double base substitution or compound variants
 19 c.3202_3203delGC
insTT
A1068L 1/2 47 MTC           dUCS
 5,2,18 c.[874G > A(;)
c.200G > A(;)
c.2944C > T]
V292M/R67H/
R982C (cis)
5/11 42 (26–70) c MTC/CCH/PHEO c          12, 24 cpathogenic
 5,7 c.[833C > A(;)
c.1465G > A]
T278N/D489N
(trans)
1/1 48 MTC           dUCS
 11,18 c.[2945G > A(;)
c.2037C > T]
R982H/P679P
(NA)
1/1 65 MTC           dUCS
 1,19 c.[56_58delTGC(;)
c.3202_3203delGC
insTT]
L19delC/
A1068L (NA)
1/1 36 MTC           dUCS
 Total   23 (17) 31 /83 48.0(26–75)            
  1. negative, dbSNP Database of Single Nucleotide Polymorphism, 1000 Genomes 1000 Genomes Project database, ExAC Exome Aggregation Consortium, gnomAD genome Aggregation Database, ACMG American College of Medical Genetics and Genomics, Ref References, D damaging, deleterious or disease_causing, P possibly damaging, T tolerated, B benign or polymorphism, MTC medullary thyroid carcinoma, PHEO pheochromocytoma, CCH C cell hyperplasia, Ref references, UCS uncertain significance
  2. a Not reported
  3. b 15 carriers with RET-S409Y including 1 with S409Y/P679P, trans, by Qi et al. reported in Ref. 7, among 6 presented with isolated MTC and/or with neck lymph node and distant metastases; 3 had elevated stimulated serum calcitonin (sCtn) or concurrent marginally elevated Ctn levels, the other remaining 6 exhibited typical Ctn/sCtn levels, and suggested as an ATA-MOD
  4. c 11 carriers with V292M/R67H/R982C from 4 families were found. Of these, 4 presented with isolated MTC/CCH (mean age 51 years; range 43–70 years), 1 presented with PHEO alone (age 26 years), the remaining 4 carriers (range 19–48 years) had no abnormality and undetectable Ctn. V292M/R67H/R982C should be considered as a weaker pathogenicity. The clinical results implied that the V292M/R67H/R982C should be considered pathogenic mutation
  5. d Clinical data showed these variants of uncertain significance
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