Multilocus Inherited Neoplasia Alleles Syndrome: a Case Series and Review

Supplementary Online Content

Whitworth J, Skytte A-B, Sunde L, et al. Multilocus inherited neoplasia alleles syndrome: a case series and review. JAMA Oncol. Published online December 10, 2015. doi:10.1001/jamaoncol.2015.4771

eMethods

eTable 1. Genes Used for Literature Search

eTable 2. MultiLocus Germline Inherited Cancer Mutations—Details of Published Cases Incorporating Those in This Article

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

Downloaded From: https://jamanetwork.com/ on 10/01/2021 eMethods

Literature review

In order to review published cases with MINAS we undertook a systematic review of the

published literature. Initially a list of inherited cancer genes (n=94) was constructed

based on the Illumina TruSight Cancer gene panel (Supplementary table 1), a diagnostic

assay developed in conjunction with the Institute of Cancer Research, London, UK to

analyse a comprehensive selection of clinically relevant genes. This was then used to

perform a Medline database search. Firstly, each gene was entered as a search term (if

in existence in the database as in the case of APC, BRCA1, BRCA2, NF1, NF2, RB1,

TP53, WT1) and a keyword to produce a list of all articles pertinent to that gene.

Secondly, the entries were then combined with the OR operator to produce 94 lists, each

of which contained the articles pertinent to all the genes except one. Thirdly, each of the

original individual gene entries was combined via the AND operator with the combination

entry that lacked that particular gene. Therefore any article referring to a given gene in

combination with any other inherited cancer gene from the list was captured. Finally, the

resulting lists were then combined to produce one entry, which was further combined via

the AND operator with the linked terms/keywords “germline mutation” OR “germline” OR

“germ-line” OR “double heterozygosity” OR “double heterozygote” OR “genetic

predisposition to disease” OR “inherited mutation” An additional PubMed search was

also performed using the search term “double heterozygote + cancer.” The 3966

resulting articles were filtered manually to assess whether they reported a case of

MINAS. Mutations described in the articles were reviewed to assess pathogenicity and

were included if they led to protein truncation, disruption of a splice site or were classed

as pathogenic in a locus specific database. It has been speculated that lower penetrance

Downloaded From: https://jamanetwork.com/ on 10/01/2021 variants may confer increased phenotypic severity when in combination with pathogenic

changes in another gene but these cases were not considered.

Downloaded From: https://jamanetwork.com/ on 10/01/2021 eTable 1. Genes Used for Literature Search

AIP ERCC2 MEN1 SBDS ALK ERCC3 MET SDHAF2 APC ERCC4 MLH1 SDHB ATM ERCC5 MSH2 SDHC BAP1 EXT1 MSH6 SDHD BLM EXT2 MUTYH SLX4 BMPR1A EZH2 NBN SMAD4 BRCA1 FANCA NF1 SMARCB1 BRCA2 FANCB NF2 STK11 BRIP1 FANCC NSD1 SUFU BUB1B FANCD2 PALB2 TMEM127 CDC73 FANCE PHOX2B TP53 CDH1 FANCF PMS1 TSC1 CDK4 FANCG PMS2 TSC2 CDKN1C FANCI PRF1 VHL CDKN2A FANCL PRKAR1A WRN CEBPA FANCM PTCH1 WT1 CEP57 FH PTEN XPA CHEK2 FLCN RAD51C XPC CYLD GATA2 RAD51D DDB2 GPC3 RB1 DICER1 HNF1A RECQL4 DIS3L2 HRAS RET EGFR KIT RHBDF2 EPCAM MAX RUNX1

Downloaded From: https://jamanetwork.com/ on 10/01/2021 eTable 2. MultiLocus Germline Inherited Cancer Mutations—Details of Published Cases Incorporating Those in This Article

Key: †Tumour type associated with mutations in gene 1 ‡Tumour type associated with mutations in gene 2 *Tumour type associated with gene 1 and gene 2 ∆ Tumour type associated with mutations in neither gene 1 or gene 2 Clinical feature counted as associated if mutation associated with increased risk and 5% lifetime risk in mutation carriers

Bold type Early age at diagnosis - Age counted as early onset if <5% risk before age of diagnosis (if figures available)

LOH Loss of heterozygosity i.e. loss of normal allele for quoted gene in tumour IHC Immunohistochemistry ER Estrogen receptor PR Progesterone receptor

Kind Clinical red Ge features with Ca Refere withi S Gene 1 Gene Gene 2 ne age in years at se nce n ex variant 2 variant 1 which noted (if repo known) rt c.131C>T p.(Ser44Phe) . Additional c.3047_3048in non- sTGAGA Breast invasive Borg et BRC pathogenic ductal carcinoma 1 1 F p.(Asn1018Met MLH1 al. 2000 A1 variant 35y (MSI low. fs*8) c.1321G>A ERPR -ve)† p.(Ala441Thr )

Breast cancer 35y (Loss of MLH1 on IHC . LOH MLH1 and BRCA1)†; Endometrial carcinoma (Loss of MLH1 on IHC. LOH c.1489dupC MLH1)‡; Ovarian Pedroni c. 300T>G BRC p.(Arg497Pro carcinoma 39y 2 et al. 1 F p.(Cys61Gly) MLH1 A1 (Loss of MLH1 on 2013 fs*6) IHC. LOH MLH1 )*; Renal clear cell carcinoma 39y∆; Breast cancer (contralateral) 46y (Loss of MLH1 on IHC. LOH and BRCA1 )‡

Downloaded From: https://jamanetwork.com/ on 10/01/2021 c.213-12A>G, Endometrial p.(Arg71Serfs* c.515dup endometroid Kast et BRC 3 1 F 21). Cryptic MSH6 p.(Leu173Thr adenocarcinoma al. 2012 A1 splice site fs*9) 46y (Loss of MSH6 on IHC)‡

Lobular and ductal carcinoma in situ 32y (ERPR +ve)†; Endometroid c.1277_1386 adenocarcinoma Thiffault c.314T>G BRC del (Exon 8 40y (No MMR 4 et al. 1 F p.(Leu105*) MSH2 A2 deficiency on IHC. 2004 deletion) MSI low)∆; Colon villotubular adenoma. 40 (Loss of MSH2 on IHC. MSI high)‡ Cutaneous malignant melanoma <55y‡; Parathyroid chief Foppiani c.2410G>A c.142C>A CDKN2 cell adenoma 55y†; 5 et al. 1 M RET p.(Val804Met) p.(Pro48Thr) A Thyroid sclerotic 2008 papillary carcinoma 55y†; Thyroid C cell hyperplasia 55y† Breast cancer 31y*; c.847C>T Breast cancer 66y*; Manouki c.7180A>T BRC p.(Arg283Cy Leiomyosarcoma of 6 an et al. 1 F p.(Arg2394*) TP53 A2 chest wall 71y (In 2007 s) breast radiotherapy field)‡ Cutaneous c.329G>T malignant Monner c.4889C>G melanoma 65y‡; BRC p.(Arg110Le 7 at et al. 1 F p.(Ser1630*) TP53 Breast cancer 69y*; A2 2007 u) Ovarian cancer 69y*; Colon cancer 74y‡ Abnormal c.2808_2811de c. secretory Ghataor lACAA parathyroid gland BRC 1064+1delG 8 he et al. 1 F p.(Ala938Profs MEN1 34y‡; Pancreastic A2 T 2007 *21) mass. Unknown histology. Non functional 35y* Cushing c.2808_2811de syndrome c. (implied pituitary Ghataor lACAA BRC 1064+1delG origin) 10y‡; 9 he et al. 1 F p.(Ala938Profs MEN1 A2 Hypercalcaemia 2007 T *21) (implied hyperparathyroidis m) 31y‡

Downloaded From: https://jamanetwork.com/ on 10/01/2021 c.2808_2811de c. Ghataor lACAA Parathyroid BRC 1064+1delG 10 he et al. 1 M p.(Ala938Profs MEN1 hyperpalsia 56y‡; A2 T 2007 *21) Breast cancer 60y†

Facial papules <28y‡; Colon carcinoma and c.1285dup multiple colon Kashiwa c.637C>T. p.(His429Pro polyps 28y†; 11 da et al. 1 F APC p.(Arg213*) FLCN Recurrent 2012 fs*27) pneumothoraces x4. Pulmonary cysts 28y (first one)‡ Retinal haemangioma x2 Gene 21y‡; Cerebellar Kilmartin c.3340 C>T deletion (in haemangioblastom 12 et al. 1 M APC p.(Arg1114*) VHL a 41y‡ Rectal 1996 offspring) carcinoma and multiple colonic polyps 41y† Pituitary tumour 38y‡; Primary hyperparathyroidis m 45y*; Papillary Mastroia c.1997A>T c.669+1G>T thyroid cancer 13 nno et 1 M RET p.(Lys666Met) MEN1 46y∆; Medullary al. 2011 thyroid cancer 46y†; Gastric carcinoid tumour 47y‡; Gastrinoma‡ Primary hyperparathyroidis m 40y*; Cushing syndrome (implied pituitary origin) 40y‡; Carcinoid Mastroia c.1997A>T c.669+1G>T tumour 40y‡; 14 nno et 1 M RET p.(Lys666Met) MEN1 Lipoma 40y‡; al. 2011 Angiofibroma 40y‡; Papillary thyroid cancer∆; Medullary thyroid cancer 40y†; Gastrinoma 41y‡

Mastroia c.1997A>T c.669+1G>T 15 nno et 1 M RET p.(Lys666Met) MEN1 No features 6y al. 2011

Primary Mastroia c.1997A>T c.669+1G>T hyperparathyroidis 16 nno et 1 F RET p.(Lys666Met) MEN1 m 13y*; Pituitary al. 2011 tumour 15y*

Downloaded From: https://jamanetwork.com/ on 10/01/2021 Neuroblastoma 0y‡; Lipoma. Abdominal wall 0y†; Haemangiomas 1y†; Macrocephaly†; Ovarian granulosa cell tumour 1y (No c.334C>G somatic PTEN or c.844C>T p.(Leu112Val). TP53 mutations. Plon et PTE p.(Arg282Trp LOH PTEN . No 17 1 F Cryptic splice TP53 al. 2008 N ) LOH TP53)∆; site Xanthoastrocytoma . Temporal lobe 3y (No somatic PTEN or TP53 mutations. No LOH PTEN or TP53)∆; Pelvic liposarcoma 4y (No somatic PTEN or TP53 mutations. LOH PTEN . No LOH TP53)∆ Multiple colonic polyps 10y‡; Subcutaneous nodules‡; Multinodular goitre 26y†; Papillary thyroid cancer, multiple nodular hyperplasia and follicular adenomas c.540dup 26y†; Diffuse lymphocytic chronic Valle et PTE c.634+5G>A p.(Gln181Thr 18 1 F APC thyroiditis†; Ovarian al. 2004 N fs*12) Morgani hidatide 15y∆; Cerebellar dysplastic gangliocytoma 26y†; Palmar keratosis 26y†; Head fibroma 26y†; Lipomas 26y†; Melanocytic neavi x2 28y†; Facial papules 28y†; Oral papillomatosis 28y†

Downloaded From: https://jamanetwork.com/ on 10/01/2021 Macrocepahly†; Papillomatous papules†; Paraganglioma. Left common c.47dup c.397C>T carotid 18y‡; Zbuk et PTE Fibrocystic breast 19 1 F p.(Tyr16*) SDHC p.(Arg133*) al. 2007 N diasease 20's†; Papillary thyroid cancer 37y†; Paraganglioma. Right carotid body 39y‡; Uterine leiomyomas 30's† Rectal carcinoma and multiple colon polyps 14y*; Jejunal adenocarcinoma x6 28y x3, 34y, 44y, 52y (Loss of MLH1 and PMS2 on IHC)∆; Duodenal c.1732_2271 adenocarcinoma c.694C>T 54y*; Congenital Lindor et del (deletion 20 1 M APC p.(Arg232*) MLH1 hypertrophy of al. 2012 exons 16-19) retinal pigment epithelium 54y†; Squamous cell carcinoma. Multiple facial∆; Pilomatricoma. Scalp 54y†; Sebaceous adenoma 54y (Loss of MLH1 and PMS2 on IHC)‡ Colon polyps x5. 4 adenomas 24y (1 dysplastic MSI c.3471- high. Loss of MSH2 c.1192dupG and MSH6 on Soravia 3474delGAGA p.(Ala398Gly IHC)†; Colon 21 et al. 1 M APC p.(Glu1157Aspf MSH2 adenocarcinoma. 2005 fs*19) s*7) Right colon 25y*; Gastric/duodenal adenoma x30 25y*; Desmoid tumour. Mesenteric 26y†

Uhrham c.3183_3187de c.255_256del mer and lACAAA p.(Phe85Leuf 22 1 M APC MSH2 Colon cancer 16y* Bignon. p.(Gln1062*) s*14) 2008

Downloaded From: https://jamanetwork.com/ on 10/01/2021 Multiple colon c.3927_3931de c.677G>A polyps (100's) 10†; Scheens l p.(Arg226Gln Tubular 23 tra et al. 1 M APC p.(1309Aspfs*4 MLH1 ). Affects adenomas with 2003 ) splicing. dysplasia 10y (Loss of MLH1 on IHC)* c.536A>G MUTYH p.(Tyr179Cys c.1784delT Colon adenomas Puijenbr (compou ) and MS p.(Leu595fs*15 x5 48y (All MSI 24 oek et 1 F nd c.1187G>A H6 stable. Retained al. 2007 ) heterozy p.(Gly396As MSH6 expression)‡ gote) p)

Uterine myomas <65y∆; Meningioma c.927delA c.756dup <65y∆; Breast Pern et BRC p.(Lys309Asnfs p.(Leu253Se invasive ductal 25 1 F PALB2 al. 2012 A1 *5) rfs*4) carcinoma. Multifocal 65y (Triple negative histology)* Macrocephaly, café au lait patches and axillary freckling 57y†; c.2410G>A Kyphoscoliosis Ercolino c.1185+1G>A p.(Val804Met 57y†; Multiple 26 et al. 1 M NF1 RET cutaneous 2014 ) neurofibromas 57y†; Thyroid C- cell hyperplasia 57y‡; Parathyroid hyperplasia 57y‡ Café au lait patches c.4107_4110du multiple cutaneous neurofibromas and Campos p c.4120C>T BRC Axillary/inguinal 27 et al. 1 F p.(Gly1371Ilefs NF1 p.(Gln1374*) A1 freckling in 2013 *4) childhood‡; Breast infiltrating duct carcinoma 35y‡

c.1961delA c.1672delC Ovarian serous Augusty BRC p.(Lys654Serfs p,(Ile558Leuf carcinoma with 28 n et al. 1 F BRCA2 A1 papillary features. 2011 *47) s*15) Bilateral 50y*

c.4829_4830 c.5266dupC Augusty del Breast cancer 40y BRC p.(Gln1756Prof 29 n et al. 2 F BRCA2 p.(Val1610Gl (Triple negative A1 s*74) 2011 yfs*4) histology)*

Downloaded From: https://jamanetwork.com/ on 10/01/2021 Breast cancer 33y (LOH BRCA2 . No c.5266dupC c.5946delT LOH BRCA1 )‡; Breast cancer 44y Bell et BRC p.(Gln1756Prof p.(Ser1982Ar 30 1 F BRCA2 (LOH BRCA2. No al. 2002 A1 s*74) gfs*22) LOH BRCA1)‡; Breast cancer 47y (LOH BRCA1 . No LOH BRCA2 )† c.6275_6276 c.5123C>A del Caldes BRC 31 1 F p.(Ala1708Glu) BRCA2 p.(Leu2092P No features 2002 A1 rofs*7)

c.6275_6276 c.5123C>A del Caldes BRC Prostate cancer 32 2 M p.(Ala1708Glu) BRCA2 p.(Leu2092P 2002 A1 66y* rofs*7)

c.6275_6276 c.5123C>A del Caldes BRC 33 1 F p.(Ala1708Glu) BRCA2 p.(Leu2092P Breast cancer 70y* 2002 A1 rofs*7)

c.6275_6276 c.5123C>A del Caldes BRC 34 1 F p.(Ala1708Glu) BRCA2 p.(Leu2092P Breast cancer 66y* 2002 A1 rofs*7)

c.6275_6276 c.5123C>A del Breast cancer 28y Caldes BRC 35 1 F p.(Ala1708Glu) BRCA2 p.(Leu2092P (No LOH BRCA1 2002 A1 rofs*7) or BRCA2)*

c.6275_6276 c.5123C>A del Caldes BRC 36 1 F p.(Ala1708Glu) BRCA2 p.(Leu2092P No features 2002 A1 rofs*7)

c.6275_6276 c.5123C>A del Caldes BRC 37 1 F p.(Ala1708Glu) BRCA2 p.(Leu2092P No features 2002 A1 rofs*7)

c.6275_6276 c.5123C>A del Caldes BRC 38 1 F p.(Ala1708Glu) BRCA2 p.(Leu2092P No features 2002 A1 rofs*7)

Downloaded From: https://jamanetwork.com/ on 10/01/2021 c.1504_1508de c.2798_2799 lTTAAA delCA Breast infiltrating Choi et BRC 39 1 F p.(Leu502Alafs BRCA2 p.(Thr933Arg duct carcinoma al. 2006 A1 *2) fs*2) 26y*

c.5946delT c.4981G>T Breast infiltrating Choi et BRC p.(Ser1982Ar 40 2 F p.(Glu1661*) BRCA2 duct carcinoma al. 2006 A1 gfs*22) 33y*

c.5266dup Breast cancer 37y*; Heidem c.5645C>G BRC p.(Gln1756Prof Breast cancer 39y*; 41 ann et 1 F BRCA2 p.(Ser1882*) A1 Ovarian cancer al. 2012 s*74) 63y*

c.5718_5719 c.68_69delAG Heidem del BRC p.(Glu23Valfs* 42 ann et 2 M BRCA2 p.(Leu1908A No features A1 17) al. 2012 rgfs*2)

c.5718_5719 c.68_69delAG Heidem del BRC p.(Glu23Valfs* Breast cancer 43 ann et 2 F BRCA2 p.(Leu1908A A1 17) 32y* al. 2012 rgfs*2)

Heidem c.962G>A c. 2231C>G Breast cancer BRC 44 ann et 3 F p.(Trp321*) BRCA2 p.(Ser744*) 31y*; Breast cancer A1 al. 2012 (contralateral) 35y*

c.3910delG Heidem c.2830A>T BRC p.(Glu1304Lysf 45 ann et 4 F BRCA2 p.(Lys944*) Breast cancer 39y* A1 al. 2012 s*3)

c.658_659del Colorectal cancer. Heidem GT BRC c.5277+1delG Caecal 58y∆; 46 ann et 5 F BRCA2 p.(Val220Ilef A1 Ovarian cancer al. 2012 s*4) 61y*

c.658_659del Heidem GT BRC c.5277+1delG 47 ann et 5 M BRCA2 p.(Val220Ilef No features A1 al. 2012 s*4)

c.3700_3704de c.1813_1814i Heidem lGTAAA nsA Cervical cancer BRC 48 ann et 6 F p.(Val1234Glnf BRCA2 p.(Ile605Asnf 26y∆; Breast A1 al. 2012 s*8) s*11) cancer 40y*

Downloaded From: https://jamanetwork.com/ on 10/01/2021 Ovarian papillary c.3487delG serous c.2685_2686de cystadenocarcinom Leegte p. BRC lAA a 40y (LOH 49 et al. 1 F BRCA2 (Asp1163Ilef A1 BRCA2)*; Breast 2005 p.(Pro897fs*5) s*5) infiltrative ductal carcinoma 45y (LOH BRCA1 )* c.2685_2686de c.4449delA Leegte BRC lAA p.(Asp1484T Breast cancer. 50 et al. 2 F BRCA2 A1 Ductal 28y* 2005 p.(Pro897fs*5) hrfs*2)

c.66_67delAG c.5946delT Leegte BRC p.(Glu23Valfs* p.(Ser1982Ar 51 et al. 3 F BRCA2 No features A1 2005 17) gfs*22)

c.5263_5264in c.5946delT Leegte sC Breast invasive BRC p.(Ser1982Ar 52 et al. 4 F p.(Ser1756Prof BRCA2 lobular carcinoma A1 gfs*22) 2005 s*74) 51y*

c.3067_3068i c.2389G>T nsA Breast Liede et BRC 53 1 F p.(Glu797*) BRCA2 p.(Asn1023L adenocarcinoma al. 1998 A1 ysfs*3) 35y*

c.7934delG Loubser c.2641G>T BRC p.(Arg2645A 54 et al. 1 M p.(Glu881*) BRCA2 No features 49y A1 2012 snfs*3)

c.7934delG Loubser c.2641G>T BRC p.(Arg2645A Breast ductal 55 et al. 1 F p.(Glu881*) BRCA2 A1 carcinoma 42y 2012 snfs*3)

c.66_67delAG c.5946delT Moslehi BRC p.(Glu23Valfs* p.(Ser1982Ar 56 et al. 1 F BRCA2 No features 36y A1 2000 17) gfs*22)

c.4285_4286in Breast infiltrating Musolin c.7738C>T BRC sG duct carcinoma 37y 57 o et al. 1 F BRCA2 p.(Gln2580*) A1 (Triple negative 2005 p.(Tyr1429*) histology)*

c.3746_3747in c.6952_6953 sA del Breast infiltrating Noh et BRC 58 1 F p.(Glu1250Argf BRCA2 p.(Arg2318Ly duct carcinoma al. 2011 A1 s*5) sfs*21) 26y*

c.3018delA c.390C>A Breast infiltrating Noh et BRC p.(Gly1007V 59 2 F p.(Tyr130*) BRCA2 duct carcinoma al. 2011 A1 alfs*36) 45y*

Downloaded From: https://jamanetwork.com/ on 10/01/2021 c.5030_5033de lCTAA c.1399A>T Breast infiltrating Noh et BRC 60 3 F p.(Thr1677Ilefs BRCA2 p.(Lys467*) duct carcinoma al. 2011 A1 *2) 35y*

Breast intraductal c.5263_5264du c.5796_5797 carcinoma 38y p delTA (Triple negative Pilato et BRC 61 1 F p.(Gln1756Prof BRCA2 p.(His1932Gl histology)*; al. 2010 A1 s*10) nfs*12) Ovarian papillary adenocarcinoma. Bilateral 42y* Breast cancer 34y*; Colorectal c.3331_3334de carcinoma. lCAAG Transverse. (No Smith et BRC c.631+2T>G 62 1 F p.(Gln1111Asnf BRCA2 loss of MMR al. 2008 A1 s*5) proteins on IHC. No microsatellite instability) 35y∆; Breast cancer 53y* c.3331_3334de lCAAG Smith et BRC c.631+2T>G 63 1 F p.(Gln1111Asnf BRCA2 No features 65y al. 2008 A1 s*5)

c.3769_3770de c.5946delT Tesorier lGA BRC p.(Ser1982Ar Breast cancer <40y 64 o et al. 1 F p.(Glu1257Glyf BRCA2 A1 gfs*22) (LOH BRCA2 )* 1999 s*9)

c.835delC Breast carcinoma. Zuradelli c.8195T>G BRC p.(His279Metfs Metaplastic 43y 65 et al. 1 F BRCA2 p.(Leu2732*) A1 (Triple negative 2010 *19) histology)*

c.3916_3917de Breast ductal cancer. Medullary Zuradelli lTT c.5380delG BRC type 30y (ERPR- 66 et al. 2 F p.(Leu1306Asp BRCA2 p.(Val1794*) A1 ve)*; Ovarian 2010 fs*23) serous papillary carcinoma 36y* Breast infiltrating duct carcinoma 2x Zuradelli c.1687C>T c.6469C>T BRC foci 46y (1 lymph 67 et al. 3 F p.(Gln563*) BRCA2 p.(Gln2157*) A1 node ERPR -ve. 1 2010 lymph node ERPR+ve)* Breast ductal c.2405_2406de carcinoma 52y Zuradelli lTG c.4285C>T (Triple negative BRC 68 et al. 4 F p.(Val802Glufs BRCA2 p.(Gln1429*) histology)*; Ovarian A1 2010 *7) serous adenocarcinoma. Bilateral 52y*

Downloaded From: https://jamanetwork.com/ on 10/01/2021 c.66_67delAG c.5946delT Friedma BRC p.(Glu23Valfs* p.(Ser1982Ar 69 n et al. 1 F BRCA2 Breast cancer 38y* A1 1998 17) gfs*22)

c.66_67delAG c.5946delT Friedma BRC p.(Glu23Valfs* p.(Ser1982Ar Ovarian cancer 70 n et al. 2 F BRCA2 A1 57y* 1998 17) gfs*22)

c.66_67delAG c.5946delT Friedma BRC p.(Glu23Valfs* p.(Ser1982Ar 71 n et al. 3 F BRCA2 No features A1 1998 17) gfs*22)

c.66_67delAG c.5946delT Friedma BRC p.(Glu23Valfs* p.(Ser1982Ar 72 n et al. 4 F BRCA2 Breast cancer 45y* A1 1998 17) gfs*22)

c.66_67delAG c.5946delT Ramus Breast cancer 48y*; BRC p.(Glu23Valfs* p.(Ser1982Ar 73 et al. 1 F BRCA2 Ovarian cancer A1 1997 17) gfs*22) 50y*

Leegte c.66_67delAG c.5946delT et al. Unkno BRC p.(Glu23Valfs* p.(Ser1982Ar 74 2005/Fr F BRCA2 Breast cancer 39y* wn A1 ank et 17) gfs*22) al. 2002

Leegte c.66_67delAG c.5946delT et al. Unkno BRC p.(Glu23Valfs* p.(Ser1982Ar 75 2005/Fr F BRCA2 Breast cancer 41y* wn A1 ank et 17) gfs*22) al. 2002

Leegte c.66_67delAG c.5946delT et al. Unkno BRC p.(Glu23Valfs* p.(Ser1982Ar Breast cancer. 76 2005/Fr F BRCA2 wn A1 Bilateral 34y* ank et 17) gfs*22) al. 2002

Leegte c.66_67delAG c.5946delT et al. Breast cancer 55y*; Unkno BRC p.(Glu23Valfs* p.(Ser1982Ar 77 2005/Fr F BRCA2 Breast cancer wn A1 ank et 17) gfs*22) (contralateral) 56y* al. 2002

Leegte c.66_67delAG c.5946delT et al. Unkno BRC p.(Glu23Valfs* p.(Ser1982Ar 78 2005/Fr F BRCA2 No features wn A1 ank et 17) gfs*22) al. 2002

Leegte c.66_67delAG c.5946delT et al. Unkno BRC p.(Glu23Valfs* p.(Ser1982Ar 79 2005/Fr F BRCA2 Breast cancer 40y* wn A1 ank et 17) gfs*22) al. 2002

Downloaded From: https://jamanetwork.com/ on 10/01/2021 Leegte c.66_67delAG c.5946delT et al. Breast cancer Unkno BRC p.(Glu23Valfs* p.(Ser1982Ar 80 2005/Fr F BRCA2 33y*; Breast cancer wn A1 ank et 17) gfs*22) (contralateral) 49y* al. 2002

Leegte c.66_67delAG c.5946delT et al. Unkno BRC p.(Glu23Valfs* p.(Ser1982Ar 81 2005/Fr F BRCA2 No features 61y wn A1 ank et 17) gfs*22) al. 2002 Breast cancer. c.66_67delAG c.5946delT Multifocal lobular Randall carcinoma 30y BRC p.(Glu23Valfs* p.(Ser1982Ar 82 et al. 1 F BRCA2 (LOH BRCA1 )*; A1 1998 17) gfs*22) Ovarian cancer 41y (LOH BRCA1 and BRCA2 )* Testicular seminoma 39y∆; Renal cell carcinoma. Chromophobe 55y†; Phaeochromocyto ma 43y‡; Gastrointestinal FLC c.1381C>T stromal tumour x2 This M c.1062+2T>G NF1 83 N p.(Arg461*) 55y‡; Malignant article peripheral nerve sheath tumour 56y‡; Multiple cutaneous neurofibromas‡; Cafe au lait patches‡; Recurrent pneumothoraces.

Rectal carcinoma 27y∆; Gastroesophageal c.526T>C adenocarcinoma This FLC c.715C>T M TP53 p.(Cys176Ar 32y∆; Renal cell 84 article N p.(Arg239Cys) g) carcinoma. Chromophobe 32y†; Facial fibrofolliculomas†.

c.1285delC Pneumothorax This FLC c.892C>T F p.(His429Thrfs* MSH2 37y†; Endometrial 85 article N p.(Gln298*) 39) cancer 52y‡.

Downloaded From: https://jamanetwork.com/ on 10/01/2021 Renal cell c.1285delC carcinoma†; This FLC c.892C>T F p.(His429Thrfs* MSH2 Colorectal polyps‡; 86 article N p.(Gln298*) 39) Multiple pneumothoraces†.

c.1285delC This FLC c.892C>T Facial M p.(His429Thrfs* MSH2 87 article N p.(Gln298*) fibrofolliculomas† 39)

Caecal cancer. Mucinous 65y†; Sigmoid cancer 67y†; Previous skin tumours including squamous carcinoma in an actinic keratosis, multiple This MLH c.306G>T M XPA c.555+8A>G seborrhoeic 88 article 1 p.(Glu102Asp) keratoses, keratoacanthomata/ squamous carcinomas x2, junctional naevi, squamous carcinoma and lentigo malignae x2‡

Breast ductal carcinoma 48y*; Cutaneous melanoma 57y†; c.5213_5216de Multiple cutaneous This BRC l c.6792C>G neurofibromas‡; F NF1 89 article A2 p.(Thr1738Ilefs p.(Tyr2264*) Malignant *2) peripheral nerve sheath tumour‡; Café au lait patch‡; Possible Lisch nodules‡.

Downloaded From: https://jamanetwork.com/ on 10/01/2021