Description of additional data files

File name: Supplementary tables.doc

Title of data:

- Supplementary Table 1S Comparison of personal and family cancer history of

Korean patients with breast cancer in the present study with those of European

populations

- Supplementary Table 2S Comparison of molecular phenotype of Korean patients with

breast cancer in the present study with those of other populations

- Supplementary Table 3S Likelihood ratios of personal and family history compared

carriers of BRCA1 and BRCA2 pathogenic variants to noncarriers

- Supplementary Table 4S Likelihood of personal and family history, pathologic

profile of breast cancer, and co-occurrence of BRCA1 VUS analyses

- Supplementary Table 5S Likelihood of personal and family history, pathologic

profile of breast cancer, and co-occurrence of BRCA2 VUS analyses

- Supplementary Table 6S BRCA1 VUS analyses using interpretation according to the

ACMG standards and guidelines

- Supplementary Table 7S BRCA2 VUS analyses using interpretation according to the

ACMG standards and guidelines

File format: MS word 97-2003

1

Supplementary Table 1S Comparison of personal and family cancer history of Korean patients with breast cancer in the present study with

those of European populations

Variable, N (%) Present Study

(Korean),

N=715

Previous study (Pashayan et al.1)a

Western European,

N=36,235

Central European,

N=4,066

Asian,

N=1,183

Personal

history

Breast cancer, Age <50 years 595 (83.2) b 15941 (44.9) 1692 (41.6) 613 (51.8)

Breast cancer, Age >50 years 118 (16.5) c 6557 (18.1) 687 (16.9) 153 (12.9)

Ovarian cancer NA 2498 (6.9) 272 (6.7) 63 (5.3)

Breast and ovarian cancer 9 (1.3) 880 (2.4) 106 (2.6) 31 (2.6)

Bilateral breast cancer 89 (12.4) 3004 (8.3) 336 (8.3) 80 (6.8)

In situ breast cancer only 58 (8.1) 2497 (6.9) 334 (8.2) 108 (9.1)

Family

history d

Breast cancer 315 (44.1) 28402 (78.5) 3134 (77.1) 776 (65.6)

Ovarian cancer 30 (4.2) 3956 (8.2) 355 (8.7) 101 (8.5)

Breast and ovarian cancer 9 (1.3) 6267 (17.3) 702 (17.3) 134 (11.3)

Other related cancer 18 (2.5) NA NA NA

NA, not applicable.

2

a In the previous study,1 all individuals who underwent clinical full-sequence BRCA1/2 analysis from November 1996 to March 2006 were included while the

present study comprised consecutive Korean patients with breast cancers who underwent full-sequence BRCA1/2 analysis from September 2001 to May 2014.

b This included all patients (age <50 years) with unilateral breast cancer, bilateral breast cancer, or breast/ovarian cancer.

c This included all patients (age >50 years) with unilateral breast cancer, bilateral breast cancer, or breast/ovarian cancer.

d This included family history of first-degree and second-degree relatives.

3

Supplementary Table 2S Comparison of molecular phenotype of Korean patients with breast cancer in the present study with those of other

populations

Molecular phenotype, % a Present Study

(Korean), N=684

Previous study (Warner et al.2) b

White, N=14,268 Hispanic, N=1,122 Black, N=1,345 Asian, N=533

Luminal A like 30.1 47.4 42.1 27.1 48.0

Luminal B like 35.1 29.8 32.6 34.0 25.8

HER2 type 7.2 7.0 8.2 9.3 10.9

Basal like 23.8 15.9 17.0 29.6 15.3

a We classified breast cancer as 4 molecular phenotype based on the St. Gallen International Expert Consensus.3 But, when data of Ki-67 expression was

insufficient, we used tumor grade as a surrogate for Ki-67 expression to differentiate between luminal A–like and luminal B–like tumors.2

b In the previous study, women patients with breast cancer (stage I to III) between January 2000 and December 2007 at National Comprehensive Cancer

Network centers were included while the present study comprised consecutive Korean patients with breast cancers who underwent full-sequence BRCA1/2

analysis from September 2001 to May 2014.

4

Supplementary Table 3S Likelihood ratios of personal and family history compared carriers of BRCA1 and BRCA2 pathogenic variants to

noncarriers

Breast cancer type Age at onset Number of family history of

cancers

LR (95% CI) for gene versus neutral type

BRCA1 BRCA2

Unilateral breast cancer <40 0 0.41 (0.21-0.79) 0.40 (0.22-0.75)

1 2.53 (1.02-6.26) 2.22 (0.90-5.53)

2 2.03 (1.01-4.09) 2.19 (1.15-4.17)

≥3 12.66 (3.26-49.21) 3.71 (0.63-21.76)

≥40 0 0.37 (0.09-1.51) 0.49 (0.16-1.55)

1 0.29 (0.04-2.09) 0.51 (0.12-2.10)

2 0.66 (0.35-1.24) 0.32 (0.14-0.77)

≥3 2.01 (0.90-4.50) 2.02 (0.94-4.35)

Bilateral breast cancer or

Breast/Ovarian cancer

Any age 0 1.41 (0.49-4.01) 1.85 (0.76-4.50)

≥1 2.53 (1.02-6.26) 5.19 (2.63-10.24)

LR, likelihood ratios; CI, confidence interval.

5

Supplementary Table 4S Likelihood of personal and family history, pathologic profile of breast cancer, and co-occurrence of BRCA1 VUS

analyses

Exon Nucleotide

change

Amino acid

change

Likelihood ratio

Personal and

family history

Pathologic profiles Co-occurrence Combined

5 c.154C>T p.Leu52Phe 0.27 0.01 1.20 3.24 x 10-3

7 c.427G>A p.Glu143Lys 0.29 0.10 1.10 3.16 x 10-2

10 c.626C>T p.Pro209Leu 0.41 0.24 1.10 0.11

11 c.824G>A p.Gly275Asp 0.41 5.01 1.10 2.24

11 c.2566T>C p.Tyr856His 3.05 x 10-3 1.66 x 10-22 6.07 x 10-4 3.08 x 10-28

11 c.2726A>T p.Asn909Ile 1.92 0.24 1.10 0.51

6

11 c.2785T>C p.Phe929Leu 1.41 0.10 1.10 0.15

11 c.3119G>A p.Ser1040Asn 0.41 3.34 1.10 1.49

11 c.3448C>T p.Pro1150Ser 0.50 1.00 x 10-3 1.31 6.59 x 10-4

11 c.3650C>G p.Ser1217Cys 0.37 0.10 1.10 4.08 x 10-2

16 c.4726G>C p.Glu1576Gln 0.37 5.101 1.10 2.04

16 c.4729T>C p.Ser1577Pro 0.44 1.00 x 10-2 1.20 5.26 x 10-3

16 c.4883T>C p.Met1628Thr 0.10 6.11 x 10-9 3.03 x 10-6 1.87 x 10-15

16 c.4985T>C p.Phe1662Ser 0.66 5.01 1.10 3.63

18 c.5137G>T p.Val1713Leu 0.41 5.01 1.10 2.24

7

22 c.5339T>C p.Leu1780Pro 0.68 0.98 1.44 0.97

8

Supplementary Table 5S Likelihood of personal and family history, pathologic profile of breast cancer, and co-occurrence of BRCA2 VUS

analyses

Exon Nucleotide

change

Amino acid change Likelihood ratio

Personal and family

history

Pathologic profiles Co-occurrence Combined

7 c.623T>G p.Val208Gly 0.51 0.58 1.11 0.32

10 c.943T>A p.Cys315Ser 2.22 1.80 1.11 4.44

10 c.1255T>C p.Cys419Arg 0.40 1.80 1.11 0.81

10 c.1568A>G p.His523Arg 0.40 1.10 1.11 0.49

10 c.1744A>C p.Thr582Pro 2.22 0.29 1.88 1.23

10 c.1889C>T p.Thr630Ile 0.40 1.47 1.11 0.66

11 c.2202G>C p.Leu734Phe 0.32 1.10 1.11 0.399

11 c.2350A>G p.Met784Val 0.64 0.68 2.27 x 10-6 9.77 x 10-7

11 c.2465G>A p.Cys822Tyr 0.51 1.47 1.11 0.83

11 c.3568C>T p.Arg1190Trp 0.32 1.80 1.11 0.65

11 c.4320A>C p.Lys1440Asn 2.02 0.56 1.11 1.26

11 c.4854T>A p.Asp1618Glu 0.20 1.93 1.23 0.47

11 c.5784A>C p.Glu1928Asp 0.40 1.80 9.93 x 10-3 7.22 x 10-3

11 c.5785A>G p.Ile1929Val 0.34 2.12 2.27 x 10-6 1.63 x 10-6

11 c.5969A>C p.Asp1990Ala 0.36 2.06 1.23 0.91

10

11 c.6029T>G p.Val2010Gly 2.19 1.47 1.11 3.58

11 c.6131G>T p.Gly2044Val 0.49 0.56 1.11 0.31

11 c.6325G>A p.Val2109Ile 0.32 1.80 1.11 0.65

12 c.6875A>C p.Glu2292Ala 1.83 NA 1.11 2.03

14 c.7052C>G p.Ala2351Gly 0.13 0.33 1.23 5.32 x 10-2

15 c.7469T>A p.Ile2490Lys 0,40 1.07 1.11 0.48

15 c.7469T>C p.Ile2490Thr 0.32 1.80 1.11 0.65

15 c.7522G>A p.Gly2508Ser 0.40 1.47 1.11 0.66

11

16 c.7691C>G p.Thr2564Ser 0.91 0.62 1.23 0.69

17 c.7814G>A p.Cys2605Tyr 2.22 0.10 1.11 0.25

18 c.8069T>A p.Val2690Asp 2.22 1.80 1.11 4.44

18 c.8187G>T p.Lys2729Asn 2.64 x 10-3 0.10 1.88 5.17 x 10-4

27 c.9934A>G p.Ile3312Val 3.37 0.25 1.11 0.92

NA, not applicable

Supplementary Table 6S BRCA1 VUS analyses using interpretation according to the ACMG standards and guidelines

Ex

on

Nucleotide

change

Amino acid change dbSNP Population data,

1000/ESP/EAC, MAF(MAF in

Computational

and prediction

Functional

data

Allelic

data

Other databases, Literatur

12

East Asian) data, PolyPhen-

2/SIFT/PROVE

AN/nsSNPAnal

yzer/MutationT

aster

ARUP/BIC/ClinVar/

HGMD/LOVD/UMD

e

5 c.154C>T p.Leu52Phe rs80357084 NA/NA/1.27 x 10-4(1.75 x 10-3) D/D/N/D/D Inconclusive None NF/ND/US/LP/ND/NF 4-9

7 c.427G>A p.Glu143Lys rs80356991 NA/NA/9.89 x 10-5(5.78 x 10-4) N/N/N/N/N NA None B/ND/ND/NF/ND/US -

10 c.626C>T p.Pro209Leu rs201596327 2.0 x 10-4 (1.0 x 10-3)/NA/8.69 x

10-6(1.19 x 10-4)

N/N/N/N/N NA None NF/NF/NF/NF/NF/NF -

11 c.824G>A p.Gly275Asp rs397509327 NA/NA/9.91 x 10-5(1.39 x 10-3) D/D/D/D/N NA None NF/NF/US/P/NF/NF 10-12

11 c.2566T>C p.Tyr856His rs80356892 3.0 x 10-3(1.39 x 10-2)/7.7 x 10-

5/1.52 x 10-3(2.08 x 10-2)

D/D/D/D/N No deleterious

effect

Present B/ND/ND/LP/ND/B

11 c.2726A>T p.Asn909Ile rs80357127 NA/NA/4.94 x 10-5(6.94 x 10-4) D/D/D/D/N NA None NF/ND/US/P/ND/US

11 c.2785T>C p.Phe929Leu NA NA/NA/NA N/N/D/N/N NA None NF/NF/NF/NF/NF/NF -

11 c.3119G>A p.Ser1040Asn rs4986852 9.78 x 10-3(0)/1.65 x 10-2/1.32 x

10-2(0)

D/N/N/N/N NA None B/ND/ND/LP/ND/B

11 c.3448C>T p.Pro1150Ser rs80357272 7.99 x 10-4(4.0 x 10-3)/NA/9.07

x 10-5(1.27 x 10-3)

D/D/D/D/D NA None NF/ND/US/P/ND/US

11 c.3650C>G p.Ser1217Cys rs398122676 NA/NA/1.65 x 10-5(2.31 x 10-4) N/N/N/D/N NA None NF/NF/US/NF/NF/NF -

16 c.4726G>C p.Glu1576Gln NA NA/NA/NA N/N/N/D/N NA None NF/NF/NF/NF/NF/NF -

13

16 c.4729T>C p.Ser1577Pro rs80356909 NA/NA/2.48 x 10-5(2.31 x 10-4) N/N/N/D/N NA None NF/ND/ND/LP/NF/US 4

16 c.4883T>C p.Met1628Thr rs4986854 2.60 x 10-3(1.19 x 10-2)/3.08 x

10-3/1.52 x 10-3(7.71 x 10-3)

N/N/N/N/N No deleterious

effect

Present B/ND/ND/LP/B/B

16 c.4985T>C p.Phe1662Ser rs28897695 NA/NA/8.24 x 10-6(1.16 x 10-4) N/N/N/D/N No deleterious

effect

None NF/ND/ND/NF/ND/NF

18 c.5137G>T p.Val1713Leu NA NA/NA/NA N/D/N/D/D NA None NF/NF/NF/NF/NF/NF -

22 c.5339T>C p.Leu1780Pro rs80357474 NA/NA/NA D/D/N/D/D Deleterious

effect

None NF/ND/US/LP/ND/NF

NA, not applicable; D, deleterious; N, neutral; NF, not found; ND, not determined; US, uncertain significance; B, benign; LB, likely benign; P, pathogenic; LP, likely pathogenic.

For interpretation of BRCA1 VUS according to the ACMG standards/guideline, population data, computational and predictive data, functional data, and alleleic data were basically used. In addition, segregation

data and de novo data could not be considered because of lack of pedigree and family testing.

Supplementary Table 7S BRCA2 VUS analyses using interpretation according to the ACMG standards and guidelines

14

Exo

n

Nucleotide

change

Amino acid

change

dbSNP Population data,

1000/ESP/EAC, MAF (MAF in

East Asian)

Computational

and prediction

data, PolyPhen-

2/SIFT/PROVEA

N/nsSNPAnalyzer

/MutationTaster b

Functional

data

Allelic data Databases,

ARUP/BIC/ClinVar/

HGMD/LOVD/UMD c

Literatur

e

7 c.623T>G p.Val208Gly rs80358865 NA/NA/5.78 x 10-5(8.10 x 10-4) D/D/N/D/D NA None NF/ND/US/NF/NF/NF 45

10 c.943T>A p.Cys315Ser rs79483201 1.60 x 10-3(7.9 x 10-3)/NA/3.74

x 10-4(5.10 x 10-3)

N/N/N/N/N NA None NF/ND/ND/LP/US/US 46-49

10 c.1255T>C p.Cys419Arg NA NA/NA/NA N/N/N/N/N NA None NF/NF/NF/NF/NF/NF -

10 c.1568A>G p.His523Arg rs80358443 NA/NA/1.25 x 10-4(1.51 x 10-3) N/N/N/D/N NA None NF/NF/LB/LP/US/US -

10 c.1744A>C p.Thr582Pro rs80358457 3.99 x 10-4(2.0 x 10-3)/NA/2.24

x 10-4(3.13 x 10-3)

D/D/N/D/N NA None B/ND/ND/P/ND/B

10 c.1889C>T p.Thr630Ile rs80358479 NA /7.8 x 10-5/1.80 x 10-4(1.17

x 10-4)

N/D/N/D/N NA None B/ND/ND/NF/B/LB

11 c.2202G>C p.Leu734Phe NA NA/NA/NA D/D/D/D/N NA None NF/NF/NF/NF/NF/NF -

11 c.2350A>G p.Met784Val rs11571653 3.59 x 10-3(1.79 x 10-2)/NA

/3.14 x 10-4(4.39 x 10-3)

N/N/N/N/N NA Present US/ND/ND/LP/ND/US

11 c.2465G>A p.Cys822Tyr NA NA/NA/NA N/N/D/N/N NA None NF/NF/NF/LP/NF/NF 4

11 c.3568C>T p.Arg1190Trp rs80358604 NA/NA/1.07 x 10-4(0) D/D/D/D/N NA None B/ND/ND/NF/ND/B -

15

11 c.4320A>C p.Lys1440Asn rs769535925 NA/NA/NA D/D/D/D/D NA None NF/NF/NF/NF/NF/US -

11 c.4854T>A p.Asp1618Glu rs80358708 NA/NA/8.35 x 10-6(1.16 x 10-4) N/N/D/N/N NA None NF/ND/US/NF/NF/NF 45

11 c.5784A>C p.Glu1928Asp rs431825335 NA/NA/NA N/N/N/N/N NA Present NF/NF/US/NF/NF/NF -

11 c.5785A>G p.Ile1929Val rs79538375 1.40 x 10-3(6.0 x 10-3)/7.7 x 10-

5/9.58 x 10-4(9.83 x 10-3)

N/N/N/N/N NA Present B/ND/LB/LP/ND/B

11 c.5969A>C p.Asp1990Ala rs148618542 2.0 x 10-4(1.0 x 10-3)/NA/4.15 x

10-5(5.78 x 10-4)

D/D/D/D/D NA None NF/NF/US/LP/NF/NF 4

11 c.6029T>G p.Val2010Gly rs80358839 NA/NA/3.32 x 10-3(4.62 x 10-4) N/D/D/D/N NA None NF/ND/US/NF/US/NF 45

11 c.6131G>T p.Gly2044Val rs56191579 5.99 x 10-4(3.0 x 10-3)/7.7 x 10-

5/4.14 x 10-3(5.78 x 10-4)

N/N/D/N/N NA None NF/ND/ND/P/NF/NF

11 c.6325G>A p.Val2109Ile rs79456940 3.99 x 10-4(2.0 x 10-3)/NA/2.75

x 10-4(3.84 x 10-3)

N/N/N/N/N NA None NF/ND/ND/LP/ND/US

12 c.6875A>C p.Glu2292Ala rs397507378 NA/NA/8.54 x 10-6(0) D/D/N/D/D NA None NF/NF/NF/NF/US/NF -

14 c.7052C>G p.Ala2351Gly rs80358932 7.99 x 10-4(4.0 x 10-3)/NA /1.32

x 10-4(1.74 x 10-3)

D/D/N/D/N NA None LB/ND/ND/LP/ND/US

15 c.7469T>A p.Ile2490Lys NA NA/NA/NA N/N/N/D/N NA None NF/NF/NF/NF/NF/NF -

15 c.7469T>C p.Ile2490Thr rs11571707 1.60 x 10-2(3.0 x 10-3)/1.62 x 10-

3/1.44 x 10-2(3.59 x 10-3)

N/N/N/D/N No

deleteriou

s effect

None NF/B/ND/LP/ND/B

15 c.7522G>A p.Gly2508Ser rs80358978 NA/NA/1.08 x 10-4(1.51 x 10-3) D/D/N/D/D NA None NF/ND/ND/P/ND/US

16

16 c.7691C>G p.Thr2564Ser rs431825355 NA/NA/3.30 x 10-5(4.63 x 10-4) N/N/N/N/N NA None NF/NF/NF/NF/NF/NF -

17 c.7814G>A p.Cys2605Tyr rs786202527 NA/NA/NA D/D/D/D/D NA None NF/NF/US/LP/NF/NF 4

18 c.8069T>A p.Val2690Asp NA NA/NA/NA D/D/N/D/D NA None NF/NF/NF/NF/NF/NF -

18 c.8187G>T p.Lys2729Asn rs80359065 2.60 x 10-3(1.19 x 10-2)/NA

/8.24 x 10-4(9.71 x 10-3)

D/D/N/N/N No

deleteriou

s effect

None B/ND/ND/LP/ND/US

27 c.9934A>G p.Ile3312Val rs80359254 NA/NA/8.25 x 10-6(1.10 x 10-3) N/N/N/N/N NA None NF/ND/US/NF/NF/NF 45

NA, not applicable; D, deleterious; N, neutral; NF, not found; ND, not determined; US, uncertain significance; B, benign; LB, likely benign; P, pathogenic; LP, likely pathogenic.

For interpretation of BRCA1 VUS according to the ACMG standards/guideline, population data, computational and predictive data, functional data, and alleleic data were basically used. In addition, segregation

data and de novo data could not be considered because of lack of pedigree and family testing.

17

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