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Table 1 Variant entries in databases dbSNP, ClinVar and HGMD, as well as allele frequencies reported by gnomAD and ESP (ALL: All, AFR: African/African American, NFE: Non-Finnish European, AMR: Latino, EAS: East Asian, SAS: South Asian, OTH: Other)

From: Trans-activation-based risk assessment of BRCA1 BRCT variants with unknown clinical significance

HGVS nucleotide variant

HGVS protein variant

Exon

Type

dbSNP

ClinVar

gnomAD

ESP

HGMD

SIFT

Align GVGD

Mutation taster

Splice prediction

Class

c.4956G>A

p.(Met1652Ile)

16

Missense

rs1799967

RCV000112434.6: Benign (ENIGMA)

RCV000048709.9: Benign/Likely benign

RCV000034756.3: Benign

RCV000476093.1: Benign

RCV000128916.4: Benign/VUS

RCV000120261.7: Benign

ALL: 1.82%

AFR: 0.18%

AMR: 0.40%

EAS: 0.012%

SAS: 3.78%

NFE: 1.53%

FIN: 5.08%

OTH: 1.66%

EA: 1.5%AA: 0.2%

CM014325(Disease-causing?)

Tolerated

C0

Polymorphism (p = 0.964)

None

1a

c.4964C>T

p.(Ser1655Phe)

16

Missense

rs80357390

RCV000112436.1: VUS

RCV000223580.1: Likely pathogenic

  

CM041700(Disease-causing)

Deleterious

C25

Disease-causing (p = 1)

None

4b

c.5075A>C

p.(Asp1692Ala)

18

Missense

rs397509222

RCV000500821.1: VUS

RCV000241473.1: VUS

  

CM169296(Disease-causing)

Deleterious

C65

Disease-causing (p = 1)

None

4

c.5095C>T

p.(Arg1699Trp)

18

Missense

rs55770810

RCV000048789.10: Pathogenic

RCV000159999.4: Pathogenic

RCV000077595.6: Pathogenic (ENIGMA)

RCV000191041.1: Pathogenic

RCV000457515.1: Pathogenic

RCV000239322.2: Pathogenic

RCV000131821.4: PathogenicRCV000148390.1: Pathogenic

ALL: 0.0024%EAS: 0.0058%

NFE: 0.0018%FIN: 0.0090%OTH: T = 0.11%

EA: 0.01%

CM041706(Disease-causing)

Deleterious

C65

Disease-causing (p = 1)

None

5b

c.5096G>A

p.(Arg1699Gln)

18

Missense

rs41293459

RCV000031217.14: Likely pathogenic

RCV000048790.6: Pathogenic/Likely pathogenic

RCV000195350.6: Pathogenic/Likely pathogenicRCV000131564.6: Pathogenic/Likely pathogenic

ALL: 0.0024%NFE: 0.0054%

 

CM034007(Disease-causing)

Deleterious

C35

Disease-causing (p = 1)

None

4

c.5100A>G

p.(Thr1700Thr)

18

Synonymous

rs45519437

RCV000199783.5: Likely benign

RCV000428938.2: Benign/Likely benign

RCV000494789.2: Likely benign (ENIGMA)

RCV000163399.2: Likely benign

ALL: 0.0028%AMR: 0.0060%SAS: 0.0032%NFE: 0.0036%

EA: 0.01%

    

None

2

c.5116G>A

p.(Gly1706Arg)

18

Missense

rs886040864

RCV000494689.1: Pathogenic

RCV000257990.3: Likely pathogenic/VUS

  

CM1612904(Disease-causing?)

Deleterious

C65

Disease-causing (p = 1)

None

4

c.5123C>T

p.(Ala1708Val)

18

Missense

rs28897696

RCV000212194.4: VUS

RCV000148393.1: VUS

RCV000031221.5: VUS

RCV000131166.5: VUS

RCV000048803.10: VUS

ALL: 0.0024%

AFR: 0.039%

EA: 0.01%AA: 0.05%

CM065004(Disease-causing)

Deleterious

C65

Disease-causing (p = 1)

None

3

c.5125G>A

p.(Gly1709Arg)

18

Missense

rs886038197

RCV000546570.2: VUS

RCV000241163.1: VUS

RCV000571176.2: VUS

   

Deleterious

C15

Disease-causing (p = 1)

None

3

c.5131A>C

p.(Lys1711Gln)

18

Missense

 

RCV000463327.1: VUS

   

Tolerated

C0

Disease-causing (p = 0.974)

None

3

c.5252G>A

p.(Arg1751Gln)

20

Missense

rs80357442

RCV000112579.2: Benign (ENIGMA)

RCV000257892.6: Benign

RCV000162992.3: Benign/Likely benign

RCV000168520.7: Benign/Likely benign/VUS

RCV000148392.1: VUS

ALL: 0.0041%

AMR: 0.0060%

NFE: 0.0072%

EA: 0.01%

CM022328(Disease-causing?)

Deleterious

C0

Disease-causing (p = 0.999)

None

1a

c.5309G>T

p.(Gly1770Val)

21

Missense

 

RCV000502156.1: Likely pathogenic

RCV000477771.1: Likely pathogenic

  

CM133533(Disease-causing)

Deleterious

C0

Disease-causing (p = 1)

None

4b

c.5326C>T

p.(Pro1776Ser)

21

Missense

rs1800757

RCV000480229.1: VUS RCV000477350.2: VUS

 

EA: 0.01%

 

Tolerated

C0

Polymorphism (p = 0.741)

None

2

c.5348T>C

p.(Met1783Thr)

22

Missense

rs55808233

RCV000048954.7: Likely benign

RCV000414204.1: VUS

RCV000129758.4: Benign/Likely benign

RCV000167822.8: Benign/Likely benign/VUS

RCV000031240.7: Likely benign

ALL: 0.012%AFR: 0.18%AMR: 0.0060%

OTH: 0.018%

AA: 0.18%

CM041721(Disease-causing?)

Deleterious

C45

Disease-causing (p = 0.999)

None

2

c.5411T>A

p.(Val1804Asp)

23

Missense

rs80356920

RCV000167770.7: Benign

RCV000162993.3: Benign/Likely benign

RCV000120302.4: Likely benign

RCV000148405.1: VUS

RCV000112647.4: Benign (ENIGMA)

ALL: 0.010%

AMR: 0.048%NFE: 0.0027%

EA: 0.02%

CM044859(Disease-causing?)

Tolerated

C0

Polymorphism (p = 1)

None

2a

c.5477A>T

p.(Glu1826Leu)

24

Missense

rs730881499

RCV000160011.1: VUS

ALL: 0.0033%

NFE: 0.0018%

FIN: 0.027%

  

Tolerated

C0

Polymorphism (p = 0.763)

None

2

c.5504G>A

p.(Arg1835Gln)

24

Missense

rs273902776

RCV000049023.6: VUS

RCV000240743.1: VUS

RCV000130437.5: VUS

RCV000112685.1: VUS

RCV000120265.3: VUS

ALL: 0.0028%

AFR: 0.013%

EAS: 0.0058%

NFE: 0.00090%

  

Tolerated

C0

Disease-causing (p = 0.965)

None

3

c.5513T>G

p.(Val1838Gly)

24

Missense

rs80357107

RCV000241502.1: Likely pathogenic

  

CM169297(Disease-causing)

Deleterious

C35

Disease-causing (p = 1)

None

4

  1. Variant predictions by SIFT, AlignGVGD and Mutation taster, as well as splicing effects predicted by SpliceSiteFinder-like, MaxEntScan, NNSPLICE and GeneSplicer. Alterations of ≥ 10% and agreement between three or more splice software were used as criteria for a variant to likely result in aberrant splicing. Class is the final classification following the ACMG 5-tier scheme, combining TA assay results and available data. Class with indications for benign (a) and pathogenic (b) were used as controls and were classified according to the ACMG criteria prior to this study
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Human Genomics

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