Clinical Actionability of Multigene Panel Testing for Hereditary Breast and Ovarian Cancer Risk Assessment

Supplementary Online Content

Desmond A, Kurian AW, Gabree M, et al. Clinical actionability of multigene panel testing for hereditary breast and ovarian cancer risk assessment. JAMA Oncol. Published online August 13, 2015. doi:10.1001/jamaoncol.2015.2690.

eFigure. Study Design

eTable 1. Cohort demographics

eTable 2. Mutation spectrum and analysis results for prospective and other mutation- positive participants

eTable 3. Gene selection criteria

eTable 4. Pathogenic and likely pathogenic non-BRCA1/2 variants identified

eTable 5. Cancer history and clinical impact for mutation carriers

eReferences

This supplementary material has been provided by the authors to give readers additional information about their work.

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eFigure1. Study Design

Initial Population: 1. Referred for Genetic Testing for HBOC (MGH, SU, BIDMC)a 2. Met NCCN “further genetic risk evaluation” criteria. 3. No known familial mutation. 4. Signed informed consent for research genetic analysis.

Multi-gene (25 or 29-gene) Other genetic testing and/or panel testing enrolled outside study period

Excluded: BRCA1/2 Gene mutation positive

Negative for deleterious Positive for deleterious Positive for deleterious mutation mutation mutation N=1006 N=40 N=23

Analyzed for potential clinical impact

aAt BIDMC, initial accrual was restricted to patients with breast cancer and excluded those who had positive clinical testing for BRCA1/2 mutations.

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 1. Cohort Demographics

MGH/SUa BIDMCb Number(%) Number(%) Total Patients 669 377 Gender Male 6(0.9) 3(0.8) Female 663(99.1) 374(99.2) Ethnicityc African 4(0.6) 13(3.4) Asian 43(6.4) 6(1.6) Asian Indian 15(2.2) 0(0) Caucasian 550(82.2) 343(91.0) Hispanic 27(4.0) 10(2.7) Multiple 17(2.5) 5(1.3) Unknown/other 13(1.9) 0(0) Personal Hx Cac,d Breast Ca 455(68.0) 377(100.0) Ovarian Ca 40(6.0) 7(1.8) Colorectal Ca 9(1.3) 1(0.3) Endometrial Ca 12(1.8) 4(1.1) Pancreatic Ca 2(0.3) 1(0.3) No personal Hx Ca 150(22.4) 0(0) Non-BRCA1/2 Mutation

Positivee 26(3.9) 14(3.7) a Mutation data reported for a subset of these patients (N=123) in [1]. b Mutation data reported in [2]. c Statistically significant differences included ethnicity (p<.01), breast cancer history (p<.001) and ovarian cancer history (p<.01) using Fisher's exact test and likelihood ratio tests. Prevalence of non-BRCA1/2 mutations was not statistically different. d Figures may not add up to 100% due to data not provided or patients with multiple primary tumors reported. e Positive for deleterious non-BRCA1/2 mutations.

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 2. Mutation spectrum and analysis results for prospective and other mutation-positive participants

Cohort Gene subset Caucas Perso Patient Family (N) High Mod./L Lynch Othe ian nal manage testing histor ment recommen -Risk ow- syndrom r e BR/O Risk ec fami y change ded Va BR/OVb lial of canc breast er cance gene r sd Prospec 3 26 8 4 37 31 20 27/36 tive (40)f Additio 5 15 1 2 21 15 13 15/22 nal (23)f Total 8 41g 9 6 58 46 33 42/58 (63) aTP53, PTEN, STK11, CDH1 bBARD1, CHEK2, PALB2, ATM, BRIP1, RAD51C, RAD51D, NBN cMLH1, MSH2, MSH6, PMS2, EPCAM dAPC, BMPR1A, SMAD4, CDK4, CDKN2A, PALLD, MET, MEN1, RET, PTCH1, VHL, MUTYH (biallelic) eDenominator indicates number of patients with first degree relatives. fNo differences between prospective and additional participants were statistically significant (p>0.05). Differences between groups were examined using Fisher's exact test and likelihood ratio tests. g41 mutations among 40 patients; one patient had concurrent ATM and BARD1 mutations.

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 3. Gene Selection Criteria

Gene Category Primary Condition (Medgen) Breast Refs Assay Cancer BRCA1 BRCA Hereditary breast and ovarian cancer 4.0-7.0 3,4 Botha BRCA2 BRCA Hereditary breast and ovarian cancer 4.0-7.0 3,4 Both PTEN High-risk PTEN hamartoma tumor syndrome 2.0-5.0 5,6 Both TP53 High-risk Li-Fraumeni syndrome (MEDGEN 4.3-9.3 7 Both STK11 High-risk Peutz-Jeghers syndrome (MEDGEN 2.0-4.0 8,9 Both CDH1 High-risk Hereditary diffuse gastric cancer 5.9-7.3 10,11 Both ATM Mod/Low Familial cancer of breast (MEDGEN 1.5-3.8 12 Both BARD1 Mod/Low Familial cancer of breast (MEDGEN unknown 13,14 Test PALB2 Mod/Low Familial cancer of breast (MEDGEN 1.4-3.9 15,16 Both BRIP1 Mod/Low Familial cancer of breast (MEDGEN 1.2-3.2 17 Both CHEK2 Mod/Low Familial cancer of breast (MEDGEN 2.7-4.82 18 Bothb NBN Mod/Low Nijmegen breakage syndrome 1.4-6.6 19,20 Both RAD51C Mod/Low Familial cancer of breast (MEDGEN 1.5-7.8 21,22 Test RAD51D OV Familial breast-ovarian cancer 1.3c 23 Both MLH1 Lynch Lynch syndrome (MEDGEN ID: 0.2-2.0 24 Both MSH2 Lynch Lynch syndrome (MEDGEN ID: 1.2-3.7 24 Both MSH6 Lynch Lynch syndrome (MEDGEN ID: 0-13 24 Both EPCAM Lynch Lynch syndrome (MEDGEN ID: 1.2-1.6 25 Bothd PMS2 Lynch Lynch syndrome (MEDGEN ID: unknown 24 Bothe APC Other Familial adenomatous polyposis unknown 26 Both BMPR1A Other Juvenile polyposis syndrome 1.3 27 Both SMAD4 Other Juvenile polyposis syndrome unknown 28 Both CDK4 Other Familial cutaneous melanoma unknown 29 Both CDKN2A Other Familial cutaneous melanoma 1.1-1.7 30 Both PALLD Other Familial pancreatic adenocarcinoma unknown 31,32 Test MET Other Hereditary papillary renal cell unknown 33 Test MEN1 Other Multiple endocrine neoplasia, type 1 unknown 34 Test RET Other Multiple endocrine neoplasia, type 2 unknown 35 Test PTCH1 Other Basal cell nevus syndrome unknown 36 Test VHL Other Von Hippel-Lindau syndrome unknown 37 Test MUTYH Other Familial adenomatous polyposis 1.0-3.4 38 Bothg a Test A: 29-gene Invitae Hereditary Cancer Syndromes Panel (version C); Test B 25- gene Myriad MyRisk b Odds ratio rather than relative risk reported in the reference. Test A reports c.1100delC only. c RAD51D was considered as an ovarian cancer risk gene (RR 6.3) d Test B does not report sequence variants, only del/dup events e Test A reports only exons 1-11 f Sequence variants only; del/dup events were not reported in this study g Considered a strictly recessive gene in this study: Only Bi-allelic findings considered

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable 4. Pathogenic and likely pathogenic non-BRCA1/2 variants identified

Patient Gene Variant 1a CDH1 c.521dupA 2 CDH1 c.1003C>T, p.R335X 3 CDH1 c.2287G>T, p.E763X 4a CDH1 c.521dupA 5 TP53 c.638G>A, p.R213Q 6 TP53 C277R 7 TP53 c.993+12T>C 8 PTEN F200V 9a CHEK2 c.1100delC 10a CHEK2 c.1100delC 11 CHEK2 c.1100delC 12 CHEK2 S428F 13 CHEK2 c. 1100delC 14 CHEK2 c. 1100delC 15a CHEK2 c.1100delC 16 CHEK2 c. 1100delC 17 CHEK2 c.1100delC 18 CHEK2 c.1100delC 19a CHEK2 c.1100delC 20a CHEK2 c.1100delC 21 CHEK2 p.I157T 22 CHEK2 c.1100delC 23 CHEK2 c.1100delC 24 ATM c.6100C>T, p.R2034X 25 ATM c.477_481delATCTC, p.S160X23 26 ATM c.318G>A 27a ATM c.5712dupA, p.Ser1905llefs*25 28 ATM c.1024_1027delAAAG, p.E343X2 29 ATM c.2250G>A 30 ATM c.9078_9079insA, p.S3027X36 31 ATM c.8035_8050delAAT...TAC, p.N2679X9 32 ATM c.8584+1G>C 33 ATM c.8266A>T, p.K2756X 34a ATM; c.5893_5897delAAAAG; p.L316 BARD1 35 PALB2 c.3113G>A, p.W1038X 36 PALB2 c.509_510delGA, p.R170X14 37 PALB2 c.3113G>A, p.W1038X 38 PALB2 c.2509G>T 39 PALB2 c.2167_2168delAT, p.M723X21 40 PALB2 c.1240C>T, p.R414X 41a PALB2 c.509_510del

Downloaded From: https://jamanetwork.com/ on 10/02/2021 42 PALB2 c.481_482del 43 RAD51C del exons 4-9 44 RAD51C c.1027-2A>G 45 RAD51C c.97_98delCA, p.Q33X3 46a NBN c.657_661del 47 NBN c.1142delC 48 BRIP1 c.627+1G>A 49 PMS2 del exon 10 50 PMS2 c.1376C>A, p.S459X 51 PMS2 c.400C>T, p.R134X 52 PMS2 c.1A>G 53 MSH2 c.1A>C 54 MSH2 c.1906G>C, p.A636P 55 MSH6 c.1789_1790insA, p.G599X8 56 MSH6 c.1367G>A, p.W456X 57b MLH1 c.2190delT, p.P731X52 58a CDKN2A c.3G>A, p14ARF 59 CDKN2A c.9_32dup24, p.P11_S12insAlaAlaGlySerSerMetGluPro 60 CDKN2A c.369C>A 61 APC c.3999del, p.Lys1333Asnfs*82 62 BMPR1A c.676-3A>C 63a MUTYH c.1187G>A (p.Gly396Asp), c.1145G>A (p.Gly382Asp) (biallelic) a [ref. 2] or b [ref. 1] reported a deleterious variant in this gene in this individual.

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eTable5. Cancer history and clinical impact for mutation carriers

Pati Age at Family Livi Testing ent first cancer ng considere history 1st d? deg ree Nu Gen Catego Personal cancer (1st, 2nd, fem Managem (Manage mb e ry cancer dx and 3rd ale ent change ment er history degree rela considere change relative tive d for considere s) s patient? d if positive?) 1 CD High Breast 55 Breast; 1 Yes. Yes. H1 Risk Lung; Prophylact Prophylact Breast Hodgki ic ic Ovary n's gastrectom gastrectom lympho y y ma; Colon 2 CD High Unaffect N/A Gastric( 2 Yes. Yes. H1 Risk ed diffuse) Prophylact Prophylact Breast ; Colon; ic ic Ovary Lung gastrectom gastrectom y y 3 CD High Breast 30 Breast; 3 Yes. Yes. H1 Risk Prostate Prophylact Prophylact Breast ; ic ic Ovary Stomac gastrectom gastrectom h y y 4 CD High Breast, 31 Breast; 4 Yes. Yes. H1 Risk Basal Melano Prophylact Prophylact Breast Cell ma; ic ic Ovary Kidney; gastrectom gastrectom Stomac y y h; Lung 5 TP5 High Leiomyo 52 Uterine; 2 Yes. Yes. 3 Risk sarcoma Thyroid Increased Increased Breast ; cancer cancer Ovary Prostate surveillanc surveillanc ; Breast e e 6 TP5 High Breast 30 Breast; 3 Yes. Yes. 3 Risk Prostate Increased Increased Breast cancer cancer Ovary surveillanc surveillanc e e

Downloaded From: https://jamanetwork.com/ on 10/02/2021 7 TP5 High Hodgkin 38 Breast; 3 Yes. Yes. 3 Risk s (HD); Pancrea Increased Increased Breast Lympho 45(BR) s; cancer cancer Ovary ma, Stomac surveillanc surveillanc Breast h e e 8 PTE High Breast, 48(BR) Melano 3 Yes. Renal Yes. N Risk Ovarian, ;48(OV ma; ultrasound Increased Breast Thyroid ) Prostate and colon thyroid, Ovary ; Colon; cancer endometria Bladder screening l and ; breast Leukem cancer ia surveillanc e 9 CH Moder Breast 60 Ocular 0 No N/A EK2 ate/Lo Melano w risk ma; BR/O Ovarian V ; Breast; Colon; Lung 10 CH Moder Breast 51 Breast; 0 No N/A EK2 ate/Lo Prostate w risk ; Lung; BR/O Thyroid V 11 CH Moder Breast 37 Prostate 1 No No EK2 ate/Lo ; w risk Mesoth BR/O elioma V 12 CH Moder Breast, 53(BR) Prostate 1 No No EK2 ate/Lo Ovarian ; ; Liver; w risk 61(OV) Leukem BR/O ia; V Colon; Stomac h 13 CH Moder Breast, 45 Breast; 1 No No EK2 ate/Lo lipoma, Lymph w risk dermatof oma; BR/O ibroma Lung; V Thyroid ; Stomac h

Downloaded From: https://jamanetwork.com/ on 10/02/2021 14 CH Moder Breast 43 Breast; 1 No No EK2 ate/Lo Endome w risk trial; BR/O Leukem V ia; Colon. Pancrea tic; Prostate 15 CH Moder Breast 44 Breast; 2 No No EK2 ate/Lo Ovarian w risk BR/O V 16 CH Moder Breast 47 Prostate 2 No No EK2 ate/Lo ; Breast; w risk Stomac BR/O h; Non- V Hodgki n's Lymph oma; Stomac h; Colon 17 CH Moder Breast 32 Breast 3 No No EK2 ate/Lo w risk BR/O V 18 CH Moder Breast 48 Breast; 4 No No EK2 ate/Lo Endome w risk trial; BR/O Esopha V geal 19 CH Moder Breast 45 Breast; 5 No No EK2 ate/Lo Colon; w risk Thyroid BR/O ; V Prostate ; Hodgki ns Lymph oma 20 CH Moder Breast (2 46 Leukem 2 No Yes.

Downloaded From: https://jamanetwork.com/ on 10/02/2021 EK2 ate/Lo primaries ia Increased w risk ) breast BR/O screening V 21 CH Moder Breast (2 50 Breast 3 No Yes. EK2 ate/Lo primaries Increased w risk ) breast BR/O screening V 22 CH Moder Colon, 44(CO) Adreno 3 Yes. Yes. EK2 ate/Lo Lung, cortical Increased Increased w risk Chondro carcino breast breast BR/O scarcoma ma; cancer screening V , Basal Breast; screening Cell Colorec tal; Lymph oma; Larynge al 23 CH Moder Rectal 37 Breast; 3 Yes. Yes. EK2 ate/Lo Basal Increased Increased w risk cell breast breast BR/O carcino cancer screening V ma; screening Lung 24 AT Moder Unaffect N/A Ovarian 5 Yes. Yes. M ate/Lo ed ; Lung; Increased Increased w risk Stomac Breast breast BR/O h; Brain Screening screening V 25 AT Moder Melanom 32(ME Breast; 1 No No M ate/Lo a, Breast L); Lung w risk 42(BR) BR/O V 26 AT Moder Breast 38 Breast; 1 No No M ate/Lo Lung w risk BR/O V 27 AT Moder Breast 35 Breast; 1 No No M ate/Lo Lung w risk BR/O V

Downloaded From: https://jamanetwork.com/ on 10/02/2021 28 AT Moder Breast 56 Breast 6 No No M ate/Lo w risk BR/O V 29 AT Moder Breast 25 Breast 1 No No M ate/Lo w risk BR/O V 30 AT Moder Breast 53 Cervica 6 No Yes. M ate/Lo l; Increased w risk Ovarian breast BR/O ; Breast; screening V Head and Neck; Neurosa rcoma 31 AT Moder Breast 50 Breast; 4 No Yes. M ate/Lo Lung; Increased w risk Head breast BR/O and screening V Neck 32 AT Moder Pancreati 69 Gall 2 No Yes. M ate/Lo c bladder; Increased w risk Leukem breast BR/O ia; screening V Breast 33 AT Moder Breast 58 Breast; 5 No Yes. M ate/Lo Skin; Increased w risk Prostate breast BR/O ; screening V Ovarian ; Lung; Thyroid ; Colon; Esopha geal 34 AT Moder Breast 41 Ovarian 1 No Yes. M; ate/Lo ; Breast; Increased BAR w risk Colon; breast D1 BR/O Pancrea screening V tic 35 PAL Moder Unaffect N/A Breast; 0 No N/A B2 ate/Lo ed Bile

Downloaded From: https://jamanetwork.com/ on 10/02/2021 w risk duct; BR/O Lung; V Throat; Liver 36 PAL Moder Breast 39 Breast; 2 No Yes. B2 ate/Lo Melano Screening w risk ma; or BR/O Ovarian mastectom V ; Colon y. 37 PAL Moder Breast 43 Breast; 2 No Yes. B2 ate/Lo Leukem Screening w risk ia or BR/O mastectom V y. 38 PAL Moder Rectal 44 Breast 2 Yes. Yes. B2 ate/Lo Bilateral Screening w risk mastectom or BR/O y mastectom V y. 39 PAL Moder Breast 39 Lung; 1 Yes. Yes. B2 ate/Lo Breast; Bilateral Screening w risk Leukem mastectom or BR/O ia; y mastectom V Cervica y. l 40 PAL Moder Breast 51 Breast; 4 Yes. Yes. B2 ate/Lo Lung; Bilateral Screening w risk Colon; mastectom or BR/O Brain y mastectom V tumor; y. Hodgki ns Lymph oma 41 PAL Moder Breast (3 52 Breast 2 Yes. Yes. B2 ate/Lo primaries Bilateral Screening w risk ) mastectom or BR/O y mastectom V y. 42 PAL Moder Breast (2 49 Neurosa 1 Yes. Yes. B2 ate/Lo primaries rcoma; Contralater Screening w risk ) Breast; al or BR/O Lung; mastectom mastectom V Bladder y y. ; Hodgki

Downloaded From: https://jamanetwork.com/ on 10/02/2021 ns Lymph oma 43 RAD Moder Ovarian 56 Ovarian 2 Yes. Yes. 51C ate/Lo ; Increased Increased w risk Stomac breast breast BR/O h; cancer screening V Colon screening 44 RAD Moder Ovarian 51 CNS; 9 Yes. Yes. 51C ate/Lo Prostate Increased Increased w risk ; breast breast BR/O Pancrea cancer screening V tic; screening Ovarian ; Breast; Lung 45 RAD Moder Renal, 39 Pancrea 2 No Yes. 51C ate/Lo Breast (RCC); tic; Increased w risk 51 (BR) Liver; breast BR/O Cervica screening V l 46 NBN Moder Breast, 54 Prostate 0 No N/A ate/Lo Pancreati ; Breast; w risk c Stomac BR/O h; V Liver; Melano ma; Lung; Bladder ; Pancrea tic 47 NBN Moder Breast 49 Breast 3 No No ate/Lo w risk BR/O V 48 BRI Moder Ovarian 64 Lung; 1 No No P1 ate/Lo Lymph w risk oma; BR/O Female V genital cancer 49 PMS Lynch Unaffect N/A Melano 2 Yes. Yes. 2 ed ma; Increased Increased

Downloaded From: https://jamanetwork.com/ on 10/02/2021 Breast; colorectal colorectal Prostate screening screening ; Ovarian ; Esopha geal 50 PMS Lynch Ovarian 45 Cancer 2 Yes. Yes. 2 unspeci Increased Increased fied colorectal colorectal screening screening 51 PMS Lynch Unaffect N/A CNS, 3 Yes. Yes. 2 ed Lymph Increased Increased oma, colorectal colorectal Melano screening screening ma, Lung 52 PMS Lynch Breast 37 None 3 Yes. Yes. 2 Increased Increased colorectal colorectal screening screening 53 MS Lynch Squamos 64 Breast; 0 Yes. N/A H2 Cell Colorec Increased Carcino tal; colorectal/ ma Bladder endometria (Vaginal) ; Brain l tumor surveillanc e 54 MS Lynch Ovarian 39 Pancrea 0 Yes. Yes. H2 tic; Increased Increased Endome colorectal/ colorectal trial; endometria surveillanc Breast; l e Renal; surveillanc Colorec e tal; Lung; Ovarian ; CNS 55 MS Lynch Ovarian, 43 Brain 1 Yes. Yes. H6 Breast (OV); tumor; Increased Increased 49 (BR) Breast; colorectal/ colorectal/ Prostate endometria endometria ; l l Bladder surveillanc surveillanc ; Colon; e e

Downloaded From: https://jamanetwork.com/ on 10/02/2021 Liver; Ovarian 56 MS Lynch Breast 47 Prostate 2 Yes. Yes. H6 ; Breast; Increased Increased Bladder colorectal/ colorectal/ ; Colon; endometria endometria Uterine l l cancer; surveillanc surveillanc Renal e e Cell Carcino ma 57 ML Lynch Breast, 35(BR) Neurobl 2 Yes. Yes. H1 Endomet ; astoma; Increased Increased rial 46(EN Basal colorectal colorectal/ DO) Cell surveillanc endometria Carcino e l ma; surveillanc Ovarian e ; Pancrea tic; Breast 58 CD Other Breast 39 Lung; 2 Yes. Yes. KN2 Heredit CNS; Pancreatic Pancreatic A ary Breast cancer cancer cancer surveillanc surveillanc e e 59 CD Other Melanom 56(ME Breast; 3 Yes. Yes. KN2 Heredit a, Breast L); Lung; Pancreatic Pancreatic A ary 67(BR) Melano cancer cancer cancer ma; surveillanc surveillanc Leukem e e ia; Pancrea tic 60 CD Other Endomet 54 Ovarian 4 Yes. Yes. KN2 Heredit rial ; Pancreatic Pancreatic A ary Pancrea cancer cancer cancer tic; surveillanc surveillanc Lymph e e oma; CNS tumor; Stomac h

Downloaded From: https://jamanetwork.com/ on 10/02/2021 61 APC Other Breast (3 44(CO) Breast; 2 Yes. Yes. Heredit primaries ; Stomac Colectomy Colectomy ary ), Colon 49(BR) h; cancer Lung; Colon; Rectal 62 BM Other Breast, 73(ME Prostate 4 Yes. Yes. PR1 Heredit Melanom L); ; Breast; Increased Increased A ary a 74(BR) Melano gastric gastric cancer ma; cancer cancer Kidney; screening screening Colon; Bladder ; Leukem ia; Multipl e Myelo ma 63 MU Other Breast 36 Prostate 2 Yes. Yes. TYH Heredit Increased Increased (bial ary colorectal colorectal lelic cancer surveillanc surveillanc ) e e

Downloaded From: https://jamanetwork.com/ on 10/02/2021 eReferences

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