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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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