Table 2 Prioritized variants identified in the HBOC cohort and its pathogenicity prediction

ATM

c.1541G > A

p.Gly514Asp

rs2235000

missense

Benign

Benign/Likely Benign

25.7

Class C65

Polymorphism

Tolerated

Probably damaging

Disease Causing

3664; 4146

c.1636C > G

p.Leu546Val

rs2227924

missense

Likely Benign

Benign/Likely Benign

11.58

Class C25

Polymorphism

Damaging

Possibly damaging

Polymorphism

3617; 3634

c.1810C > T

p.Pro604Ser

rs2227922

missense

Uncertain Significance

Benign/Likely Benign

23.3

Class C65

Probably polymorphism

Tolerated

Possibly damaging

Disease Causing

2775

c.2442C > A

p.Asp814Glu

rs3218695

missense

Likely Benign

Benign

15.88

Class C35

Polymorphism

Tolerated

Benign

Polymorphism

2753; 2784

c.2572 T > C

p.Phe858Leu

rs1800056

missense

Uncertain Significance

Conflicting interpretations of pathogenicity

13.50

Class C15

Polymorphism

Damaging

Possibly damaging

Polymorphism

4268

c.4258C > T

p.Leu1420Phe

rs1800058

missense

Uncertain Significance

Conflicting interpretations of pathogenicity

15.47

Class C15

Polymorphism

Tolerated

Benign

Disease Causing

3650

c.5557G > A

p.Asp1853Asn

rs1801516

missense

Benign

Benign/Likely Benign

23.2

Class C15

Polymorphism

Tolerated

Benign

Polymorphism

2699; 2724; 2775; 3002; 3132 (homoz); 3141; 3166; 3187; 3728 (homoz); 4063; 4133; 4135; 4137; 4138 (homoz); 4147; 4226 (homoz)

c.6995 T > C

p.Leu2332Pro

rs4988111

missense

Likely Benign

Benign/Likely Benign

15.87

Class C65

Polymorphism

Tolerated

Benign

Polymorphism

3617; 3634

c.7740A > C

p.Arg2580Ser

rs199915459

missense

Uncertain Significance

Uncertain significance

15.65

Class C65

Pathogenic

Tolerated

Benign

Disease Causing

3671

c.5558A > T

p.Asp1853Val

rs1801673

missense

Uncertain Significance

Conflicting interpretations of pathogenicity

24.2

Class C65

Pathogenic

Damaging

Possibly damaging

Disease Causing

4186; 4264

ATR

c.2794C > A

p.Pro932Thr

–

missense

Uncertain Significance

–

27.0

Class C35

Pathogenic

Damaging

Probably damaging

Disease Causing

4020

c.7300C > G

p.Pro2434Ala

rs33972295

missense

Likely Benign

Benign/Likely Benign

23.5

Class C25

Polymorphism

Damaging

Probably damaging

Disease Causing

4228

c.946G > A

p.Val316Ile

rs28897764

missense

Likely Benign

Benign/Likely Benign

18.61

Class C25

Probable polymorphism

Tolerated

Benign

Disease Causing

2726; 3116; 3671; 3703; 4228

BARD1

c.-83C > T

–

rs71579840

5’UTR premature start codon gain

Likely Benign

–

8485

–

–

–

–

–

3002

c.1972C > T

p.Arg658Cys

rs3738888

missense

Uncertain Significance

Benign/Likely Benign

26.5

Class C65

Probably pathogenic

Damaging

Probably damaging

Disease Causing

3671

c.1268A > G

p.Lys423Arg

rs749383704

missense

Uncertain Significance

Uncertain significance

21.8

Class C25

Probably pathogenic

Tolerated

Benign

Disease Causing

2995

c.764A > G

p.Asn255Ser

rs138904906

missense

Likely Benign

Uncertain significance

16.75

Class C45

Polymorphism

Tolerated

Probably damaging

Polymorphism

3716

c.716 T > A

p.Leu239Gln

rs200359745

missense

Likely Benign

Uncertain significance

1061

Class C65

Probably pathogenic

Tolerated

Benign

Polymorphism

3051

BRCA1

c.*421G > T

–

rs8176318

3’UTR

Benign

Benign

4.78

–

–

–

–

–

2697 (homoz); 2699; 2742; 2750; 2753; 2779; 2801; 2815; 2972; 2977; 3002; 3056; 3078; 3097; 3114; 3115; 3116; 3132; 3141; 3166; 3227; 3462; 3617; 3671; 3703; 3728; 3806; 3842; 3897; 4016; 4020; 4135; 4138; 4146; 4147; 4161; 4166; 4177; 4220; 4226; 4228; 4279

c.3119G > A

p.Ser1040Asn

rs4986852

missense

Likely Benign

Benign

14.86

Class C45

Polymorphism

Tolerated

Probably damaging

Polymorphism

2699; 2785; 2995; 3002; 3114; 3876; 4020; 4037; 4132

c.5019G > A

p.Met1673Ile

rs1799967

missense

Benign

Benign

22.0

Class C0

Probable polymorphism

Tolerated

Benign

Disease Causing

3897

c.4598G > T

p.Ser1533Ile

rs1800744

missense

Likely Benign

Benign

16.14

Class C65

Polymorphism

Damaging

Possibly damaging

Polymorphism

3113

c.1648A > C

p.Asn550His

rs56012641

missense

Likely Benign

Benign

17.67

Class C65

Polymorphism

Damaging

Probably damaging

Polymorphism

4132

c.1067A > G

p.Gln356Arg

rs1799950

missense

Benign

Benign

17.80

Class C35

Polymorphism

Damaging

Probably damaging

Polymorphism

2724; 2775; 3187; 3703; 4133; 4139

c.2077G > A

p.Asp693Asn

rs4986850

missense

Benign

Benign

15.84

Class C15

Polymorphism

Damaging

Benign

Polymorphism

2815; 2977; 3097; 3116; 3671; 4122; 4220

c.5507G > A

p.Trp1836Ter

rs80356962

stop gained

Pathogenic

Pathogenic

44

–

Pathogenic

–

–

Disease Causing

3051

c.5329dupC

p.Gln1756Profs*74

rs397507247

frameshift

Pathogenic

Pathogenic

35

–

–

–

–

–

2812; 3132; 3141; 3155; 3639; 3722; 3728; 4093; 4135; 4137; 4186

c.3331_3334delCAAG

p.Gln1111Asnfs*5

rs80357701

frameshift

Pathogenic

Pathogenic

23.7

–

–

–

–

–

2723

c.2612C > T

p.Pro871Leu

rs799917

missense

Benign

Benign

17.97

Class C65

–

Tolerated

Benign

Polymorphism

2697 (homoz); 2699; 2724; 2726; 2742 (homoz); 2750; 2753; 2779 (homoz); 2801; 2812; 2815; 2972; 2977; 3002; 3056 (homoz); 3078 (homoz); 3083; 3097; 3114; 3115 (homoz); 3116 (homoz); 3132; 3141; 3166; 3227; 3441(homoz); 3462; 3617(homoz); 3650(homoz); 3651; 3664(homoz); 3671; 3703; 3728; 3782; 3802; 3806; 3842(homoz); 3897; 3920; 4016; 4020; 4037; 4063; 4093; 4122; 4135; 4138; 4139; 4144; 4146(homoz); 4147; 4161; 4166 (homoz); 4177; 4186 (homoz); 4214; 4220; 4226 (homoz); 4228; 4250 (homoz); 4262; 4268 (homoz); 4279

c.3548A > G

p.Lys1183Arg

rs16942

missense

Benign

Benign

Class C25

–

Tolerated

Benign

Polymorphism

2697 (homoz); 2699; 2742; 2750; 2753; 2801; 2815; 2972; 2977; 3002; 3056; 3078 (homoz); 3097; 3114; 3116; 3141; 3166; 3462; 3617 (homoz); 3651; 3703; 3806; 3842 (homoz); 3897; 4016; 4020; 4122; 4135; 4138; 4146; 4161; 4166; 4262; 4268 (homoz); 4279

c.4900A > G

p.Ser1613Gly

rs1799966

missense

Benign

Benign

Class C55

Polymorphism

Damaging

Possibly damaging

Polymorphism

2697; 2699; 2742; 2750; 2753; 2779; 2784; 2801; 2815; 2972; 2977; 3002; 3056; 3078 (homoz); 3097; 3114; 3115; 3116; 3132; 3141; 3166; 3227; 3462; 3617 (homoz); 3651; 3671; 3703; 3728; 3782; 3806; 3842 (homoz); 3897; 4016; 4020; 4122; 4135; 4138; 4146; 4147; 4161; 4166; 4177; 4220; 4226; 4228; 4262; 4268 (homoz); 4279

c.536A > G

p.Tyr179Cys

rs56187033

missense

Likely Benign

Benign

24.7

Class C65

Pathogenic

Damaging

Probably damaging

Disease Causing

4132

c.591C > T

p.Cys197Cys

rs1799965

splice region

Likely Benign

Uncertain significance

14.63

–

Probably pathogenic

–

–

–

4063

c.3113A > G

p.Glu1038Gly

rs16941

missense

Benign

Benign

22.2

Class C65

Polymorphism

Damaging

Possibly damaging

Polymorphism

2697; 2699; 2742; 2750; 2753; 2779; 2784; 2801; 2815; 2972; 2977; 3002; 3056; 3078 (homoz); 3097; 3114; 3115; 3116; 3132; 3141; 3166; 3227; 3462; 3617 (homoz); 3651; 3671; 3703; 3728; 3782; 3806; 3842; 3897; 4016; 4020; 4122; 4135; 4138; 4146; 4147; 4161; 4166; 4220; 4226; 4228; 4262; 4268 (homoz); 4279

BRCA2

c.156_157insAlu

–

–

insertion

Pathogenic

Pathogenic

–

–

–

–

–

–

c.811G > A

p.Gly271Arg

rs786204274

missense

Uncertain Significance

Conflicting interpretations of pathogenicity

20.6

Class C65

Probably pathogenic

Damaging

Benign

Polymorphism

2977

c.3869G > A

p.Cys1290Tyr

rs41293485

missense

Likely Benign

Benign

14.39

Class C65

Probably pathogenic

Tolerated

Benign

Polymorphism

3662

c.4258G > T

p.Asp1420Tyr

rs28897727

missense

Likely Benign

Benign

15.81

Class C65

Polymorphism

Damaging

Benign

Polymorphism

3649

c.6100C > T

p.Arg2034Cys

rs1799954

missense

Likely Benign

Benign

20.4

Class C65

Polymorphism

Damaging

Possibly damaging

Polymorphism

3441; 3617; 4279

c.8149G > T

p.Ala2717Ser

rs28897747

missense

Likely Benign

Benign

15.38

Class C65

Polymorphism

Tolerated

Possibly damaging

Polymorphism

3002

c.8850G > T

p.Lys2950Asn

rs28897754

missense

Uncertain Significance

Conflicting interpretations of pathogenicity

22.4

Class C65

Probable polymorphism

Damaging

Probably damaging

Disease Causing

2781

c.865A > C

p.Asn289His

rs766173

missense

Benign

Benign

17.23

Class C65

Polymorphism

Damaging

Probably damaging

Polymorphism

2995; 3051; 3056; 3651; 3722; 4166

c.2808_2811delACAA

p.Ala938Profs*21

rs80359351

frameshift

Pathogenic

Pathogenic

24.3

–

–

–

–

–

4147

c.8851G > A

p.Ala2951Thr

rs11571769

missense

Likely Benign

Benign

26.2

Class C55

Polymorphism

Damaging

Probably damaging

Disease Causing

3051

c.9026_9030delATCAT

p.Tyr3009Serfs*7

rs80359741

frameshift

Pathogenic

Pathogenic

–

–

–

–

–

2785

c.9382C > T

p.Arg3128Ter

rs80359212

stop gained

Pathogenic

Pathogenic

48

–

Pathogenic

–

–

Disease Causing

4262

c.9976A > T

p.Lys3326Ter

rs11571833

stop gained

Likely Benign

Benign

36

–

Pathogenic

–

–

Disease Causing

3650

c.8324 T > G

p.Met2775Arg

rs80359073

missense

Uncertain Significance

Conflicting interpretations of pathogenicity

24.1

Class C65

Pathogenic

Tolerated

Benign

Disease Causing

3116

BRIP1

c.3693A > G

p.Ile1231Met

rs876659290

missense

Uncertain Significance

Uncertain significance

13.29

Class C0

Polymorphism

Damaging

Benign

Polymorphism

3132; 3728

c.517C > T

p.Arg173Cys

rs4988345

missense

Likely Benign

Benign/Likely Benign

24.9

Class C65

Pathogenic

Damaging

Probably damaging

Disease Causing

4122; 4173

c.2220G > T

p.Gln740His

rs45589637

missense

Likely Benign

Uncertain significance

12.53

Class C15

Probably pathogenic

Damaging

Probably damaging

Disease Causing

3078

CHEK2

c.410G > A

p.Arg137Gln

rs368570187

missense

Likely Benign

Likely Benign

16.54

Class C35

Probable polymorphism

Tolerated

Benign

Disease Causing

3116

c.480A > G

p.Ile160Met

rs575910805

missense

Uncertain Significance

Conflicting interpretations of pathogenicity

22.6

Class C0

Probable polymorphism

Damaging

Probably damaging

Disease Causing

3097

FAM175A/ABRAXAS1

c.489G > T

p.Arg163Ser

rs535462791

missense

Uncertain Significance

–

22.3

Class C65

Pathogenic

Tolerated

Possibly damaging

Disease Causing

3187

c.1042G > A

p.Ala348Thr

rs12642536

missense

Benign

–

13.44

Class C55

Polymorphism

Damaging

Possibly damaging

Polymorphism

2697; 2699; 2723; 2724; 2726; 2742; 2750; 2754 (homoz); 2775; 2779; 2781 (homoz); 2784 (homoz); 2812; 2972; 2977; 3002; 3078; 3097; 3113 (homoz); 3114 (homoz); 3115; 3132 (homoz); 3141 (homoz), 3155 (homoz); 3166 (homoz); 3441; 3462; 3617; 3634; 3639; 3649 (homoz); 3651; 3662; 3706; 3716; 3722; 3728 (homoz); 3761; 3772; 3806; 3876; 3897; 3920; 4016; 4037; 4063; 4093; 4132 (homoz); 4137; 4144; 4145; 4147; 4161; 4166; 4177; 4226 (homoz); 4228; 4250; 4259; 4264; 4279

MRE11

c.1011C > G

p.Ser337Arg

rs115244417

missense

Likely Benign

Benign

21.9

Class C65

Probable polymorphism

Tolerated

Benign

Disease Causing

4135

c.2101A > G

p.Met701Val

rs1805362

missense

Likely Benign

Benign/Likely Benign

16.49

Class C15

Polymorphism

Damaging

Benign

Disease Causing

3650

NBN

c.202 T > G

p.Leu68Val

rs1200599843

missense

Uncertain Significance

Uncertain significance

15.95

Class C25

Polymorphism

Tolerated

Benign

Disease Causing

2785

c.797C > T

p.Pro266Leu

rs769420

missense

Likely Benign

Benign

24.6

Class C65

Polymorphism

Damaging

Probably damaging

Disease Causing

3078

PALB2

c.2794G > A

p.Val932Met

rs45624036

missense

Likely Benign

Benign/Likely Benign

25.3

Class C15

Polymorphism

Tolerated

Probably damaging

Disease Causing

3842

c.53A > G

p.Lys18Arg

rs138789658

missense

Uncertain Significance

Conflicting interpretations of pathogenicity

24.3

Class C25

Polymorphism

Damaging

Probably damaging

Polymorphism

3897; 4037

c.949A > C

p.Thr317Pro

rs587780223

missense

Likely Benign

Uncertain significance

4.012

Class C35

Polymorphism

Tolerated

Possibly damaging

Polymorphism

4139

RAD51

c.164C > T

p.Ala55Val

rs145617142

missense

Uncertain Significance

Uncertain significance

23.6

Class C55

Probable polymorphism

Tolerated

Possibly damaging

Disease Causing

3116

UIMC1

c.43C > T

p.Arg15Trp

rs13167812

missense

Uncertain Significance

–

22.5

Class C65

Polymorphism

Damaging

Probably damaging

Polymorphism

2750; 4250

c.1304C > T

p.Pro435Leu

rs3733876

missense

Benign

–

23.8

Class C65

Polymorphism

Damaging

Probably damaging

Polymorphism

2699; 2724; 2754; 2815; 3056; 3083; 3132 (homoz); 3634; 3649; 3671; 3761; 3842; 3920; 4020; 4063 (homoz); 4138; 4173; 4214

MLH1

c.306G > A

p.Glu102Glu

rs63751665

splice region

Likely Benign

uncertain significance

22.4

–

Pathogenic

–

–

Disease Causing

4020

c.637G > A

p.Val213Met

rs2308317

missense

Likely Benign

Benign

23.9

Class C15

Polymorphism

Tolerated

Possibly damaging

Disease Causing

4020

c.1217G > A

p.Ser406Asn

rs41294980

missense

Likely Benign

Benign

13.09

Class C45

Polymorphism

Tolerated

Possibly damaging

Polymorphism

2963

c.2146G > A

p.Val716Met

rs35831931

missense

Likely Benign

Benign

24.4

Class C15

Probable polymorphism

Damaging

Probably damaging

Disease Causing

2754

MSH2

c.2500G > A

p.Ala834Thr

rs63750757

missense

Likely Benign

Likely Benign

33.00

Class C55

Pathogenic

Damaging

Probably damaging

Disease Causing

4214

c.380A > G

p.Asn127Ser

rs17217772

missense

Benign

Benign

22.7

Class C45

Probable polymorphism

Damaging

Possibly damaging

Disease Causing

3650; 3920; 4146; 4228

c.965G > A

p.Gly322Asp

rs4987188

missense

Likely Benign

Benign

23.0

Class C65

Probable polymorphism

Tolerated

Possibly damaging

Disease Causing

2815; 3113; 3441; 4264

MSH6

c.1186C > G

p.Leu396Val

rs2020908

missense

Likely Benign

Benign

16.97

Class C25

Polymorphism

Tolerated

Possibly damaging

Disease Causing

2699; 2754

c.2633 T > C

p.Val878Ala

rs2020912

missense

Likely Benign

Benign

10.23

Class C55

Polymorphism

Tolerated

Benign

Disease Causing

4147

PMS2

c.59G > A

p.Arg20Gln

rs10254120

missense

Benign

Benign

16.65

Class C35

Polymorphism

Tolerated

Possibly damaging

Polymorphism

4146; 2963; 3097; 3116; 3722; 3782; 3806; 4137; 4145; 4220; 4262

c.2374G > A

p.Asp792Asn

rs587781265

missense

Uncertain Significance

Uncertain significance

29.8

Class C15

Probably pathogenic

Damaging

Probably damaging

Disease Causing

3802

c.2350G > A

p.Asp784Asn

rs143340522

missense

Uncertain Significance

Uncertain significance

27.8

Class C15

Polymorphism

Damaging

Probably damaging

Disease Causing

4264

c.2149G > A

p.Val717Met

rs201671325

missense

Uncertain Significance

Conflicting interpretations of pathogenicity

20.7

Class C15

Probable polymorphism

Damaging

Probably damaging

Disease Causing

3116; 3462

c.1866G > A

p.Met622Ile

rs1805324

missense

Likely Benign

Benign

18.96

Class C0

Polymorphism

Tolerated

Possibly damaging

Disease Causing

3772

c.1688G > T

p.Arg563Leu

rs63750668

missense

Likely Benign

Benign/Likely Benign

10.65

Class C65

Polymorphism

Tolerated

Possibly damaging

Polymorphism

2972; 3227; 4016

CDH1

c.1849G > A

p.Ala617Thr

rs33935154

missense

Likely Benign

Conflicting interpretations of pathogenicity

15.13

Class C55

Polymorphism

Tolerated

Benign

Disease Causing

3664; 4145; 4166

TP53

c.1010G > A

p.Arg337His

rs121912664

missense

Likely Pathogenic

Pathogenic

22.6

Class C25

–

Damaging

Probably damaging

Disease Causing

2699; 3056; 3227; 3662; 4264

c.818G > A

p.Arg273His

rs28934576

missense

Likely Pathogenic

Pathogenic/Likely pathogenic

24.0

Class C25

Pathogenic

Damaging

Probably damaging

Disease Causing

3227