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Table 4 Most interesting variants. All variants were heterozygous. Clear pathogenic mutations are shown in bold

From: Diagnostic yield and clinical utility of a comprehensive gene panel for hereditary tumor syndromes

Patient ID

Sex

Age at last contact

Gene

Mutation (heterozygous)

Predicted gene phenotype

Phenotype of patient

A) Variants identified in addition to a known germline mutation (group K)

Patient with two additional truncating mutations

 49197

m

1

NF1 (NM_001042492.2)

c.4107C > A;p.Tyr1369*

Neurofibromatosis type 1

LFS (TP53 mutation): rhabdomyosarcoma and neuroblastoma (1 y)

WRN (NM_000553.4)

c.4216C > T;p.Arg1406*

Werner syndrome

Patients with one additional truncating mutation

 41393

f

23

CHEK2 (NM_007194.3)

c.1100delC;p.Thr376Metfs*15

susceptibility breast cancer

HDGC (CDH1 mutation)

 35145

f

48

ERCC3 (NM_000122.1)

c.1421dup;p.Asp474Glufs*2

susceptibility breast cancer (biallelic mutations: Xeroderma pigmentosum (B))

HNPCC (MSH6 mutation)

 38982

m

30

FANCD2 (NM_033084.3)

c.990-1G > A

cancer susceptibility? (biallelic mutations: Fanconi anaemia (D2))

MAP (MUTYH mutations)

 34429

m

59

PALLD (NM_001166109.1)

c.2269C > T;p.Gln757*

susceptibility pancreatic cancer

HNPCC (MSH2 mutation)

 30560

m

26

SDHA (NM_004168.3)

c.1432_1432 + 1del;p.?

hereditary paraganglioma-pheochromocytoma syndrome

HNPCC (MSH2 mutation)

 32679

f

32

XPC (NM_004628.4)

c.622-2A > G

cancer susceptibility? (biallelic mutations: Xeroderma pigmentosum (C))

MAP (MUTYH mutations)

Patients with additional potential pathogenic missense / stoploss variants

 45126

f

53

BRCA1 (NM_007300.3)

c.5068G > T;p.Ala1690Ser

HBOC

HDGC (CDH1 mutation); gastric and breast cancer, sister breast cancer

 9691

f

59

MLH1 (NM_000249.3)

c.65G > C;p.Gly22Ala

HNPCC

JPS (SMAD4 mutation)

 47360

f

24

MSH2 (NM_000251.2)

c.1607A > G;p.Asn536Ser

HNPCC

JPS (BMPR1A mutation)

 36206

m

57

MSH6 (NM_000179.2)

c.3600A > G;p.Ile1200Met

HNPCC

FAP (APC mutation), two siblings CRC (~  55 y)

 24320

f

68

MSH6 (NM_000179.2)

c.3664 T > G;p.Phe1222Val

HNPCC

FAP (APC mutation), CRC (68 y), sister CRC (< 64 y)

 29267

f

65

POLE (NM_006231.3)

c.861 T > A;p.Asp287Glu

PPAP

PJS (STK11 mutation)

 44792

m

39

RAD51B (NM_133509.3)

c.1155A > T;p.*385Tyrext*64

breast cancer

HNPCC (MSH2 mutation)

B) Newly identified variants in patients with previously unknown cause (group U)

Patients with likely pathogenic mutations

 26356

f

9

PMS2 (NM_000535.5)

c.1A > T;p.Met1?

constitutional mismatch repair deficiency syndrome

multiple tumors: lymphoma (9 y), ALL, CRC (11 y), glioblastoma (15 y); two siblings died because of medulloblastoma / glioblastoma and ALL / astrocytoma

c.2117delA;p.Lys706Serfs*19

 38569

m

58

POLD1 (NM_002691.3)

c.1379 T > G;p.Lys460Arg

PPAP

adenomatous polyposis (58 y, >  50 colorectal adenomas) + renal cancer (59 y)

PMS2 (NM_000535.5)

c.2153 T > C;p.Leu718Pro

HNPCC

 40816

f

33

PTEN (NM_000314.4)

c.83 T > C;p.Ile28Thr

Cowden syndrome

CRC (32 y), duodenal lymphangiectasis, liver hemangioma, polyps or cysts in the ovary and polyps in the cervix uteri; paternal grandmother: cancer of the cervix uteri, CRC, and gastric cancer (> 70 y)

Patients with two potential pathogenic variants in different genes (at least one truncating mutation)

 13225

m

67

BARD1 (NM_000465.3)

c.1690C > T;p.Gln564*

susceptibility breast cancer and neuroblastoma

adenomatous + hyperplastic polyps, brother CRC (40 y)

XRCC3 (NM_001100119.1)

c.954_957del; p.Ser319Profs*49

susceptibility several cancer types

 44298

m

73

FANCF (NM_022725.3)

c.1087C > T;p.Gln363*

cancer susceptibility? (biallelic mutations: Fanconi anaemia (F))

duodenal polyposis (n = 15, only one was investigated histologically: adenoma), further polyps in small bowel, two colorectal adenomas (73 y)

BMPR1A (NM_004329.2)

c.712C > G;p.Arg238Gly

juvenile polyposis syndrome

 38124

m

62

MLH3 (NM_001040108.1)

c.1798C > T;p.Arg600*

HNPCC (?)

member of a family with suspected hyperplastic polyposis syndrome in one cousin, several other family members have some colorectal polyps or colorectal cancer. For patient 38124 only some polyps are reported, no histologic report is available. Five other affected family members have been also investigated with the gene panel, but no one else carries the variants in MLH3 or MUTYH

MUTYH (NM_001128425.1)

c.667A > G;p.Ile223Val

MUTYH-associated polyposis (biallelic mutations)

 35847

f

64

POLE (NM_006231.3)

c.6623del;p.Gln2208Argfs*4

PPAP

adenomatous polyps + familial CRC + other tumors

APC (NM_000038.5)

c.5009C > T;p.Ala1670Val

FAP

Patients with truncating mutations

 15263

m

71

ATM (NM_000051.3)

c.5932G > T;p.Glu1978*

susceptibility breast cancer (biallelic mutations: Ataxia-Telangiectasia)

hyperplastic polyposis (father of ID 48355)

 48355

f

55

ATM (NM_000051.3)

c.5932G > T;p.Glu1978*

susceptibility breast cancer (biallelic mutations: Ataxia-Telangiectasia)

hyperplastic polyposis (daughter of ID 15263)

 45647

f

59

BRIP1 (NM_032043.2)

c.2684_2687delCCAT;p.Ser895*

susceptibility breast and ovarian cancer (biallelic mutations: Fanconi anaemia (J))

hyperplastic polyposis, father pancreatic cancer

 46448

f

28

CHEK2 (NM_007194.3)

c.444 + 1G > A

susceptibility breast cancer

medullary thyroid cancer (27 y)

 44401

f

73

CHEK2 (NM_007194.3)

c.1100delC;p.Thr376Metfs*15

susceptibility breast cancer

follicular thyroid cancer (63 y), breast cancer (70 y), paraganglioma (72 y), renal angiomyolipoma

 48835

m

32

CHEK2 (NM_007194.3)

c.1100delC;p.Thr376Metfs*15

susceptibility breast cancer

papilly thyroid cancer, NHL (both 31 y), in family thyroid, prostatic and breast cancer

 32119

f

64

CHEK2 (NM_007194.3)

c.1100delC;p.Thr376Metfs*15

susceptibility breast cancer

thyroid cancer, breast cancer (55 y)

 22715

f

67

CHEK2 (NM_007194.3)

c.1555C > T;p.Arg519*

susceptibility breast cancer

uterine cancer (32 y), several adenomas, two with high grade dysplasia (62 + 71 y), son with colorectal polyps

 47863

f

61

EXT1 (NM_000127.2)

c.1483C > T;p.Gln495*

multiple osteochondromas / exostoses

several tumors in family

 10317

m

35

FANCE (NM_021922.2)

c.248 + 2dupT

biallelic mutations: Fanconi anaemia

sarcoma (35 y); in family: neuroblastoma, testicular cancer, bronchial cancer

 19347

f

61

FANCL (NM_001114636.1)

c.1111_1114dupATTA; p.Thr372Asnfs*13

biallelic mutations: Fanconi anaemia

bilateral breast cancer (43 + 53 y), bronchial cancer (61 y); in family: sarcoma, uterine cancer, pancreatic cancer, bronchial cancer

 47257

f

56

RAD51C (NM_058216.2)

c.706-1G > A

hereditary breast and ovarian cancer

two synchronous CRCs, 10 colorectal adenomas; endometrial cancer in family

 28219

m

48

SDHA (NM_004168.3)

c.995dup;p.Val333Cysfs*8

hereditary paraganglioma-pheochromocytoma syndrome

polyposis

 10083

m

33

XPC (NM_004628.4)

c.780-1G > A

biallelic mutations: Xeroderma pigmentosum (C)

suspected LFS

Patients with potential pathogenic missense variants

 16335

m

40

APC (NM_000038.5)

c.1631 T > C;p.Ile544Thr

FAP

suspected LFS

 37416

m

29

APC (NM_000038.5)

c.4292 T > A;p.Met1431Lys

FAP

early CRC (before 30y), MSS in tumor tissue

 37982

m

38

APC (NM_000038.5)

c.281G > A;p.Arg94His

FAP

CRC (before 40y), MSS in tumor tissue

 44716

m

52

APC (NM_000038.5)

c.7645C > T;p.Arg2549Cys

FAP

Gastrointestinal stromal tumor

 17052

f

46

BMPR1A (NM_004329.2)

c.1022G > A;p.Gly341Asp

juvenile polyposis syndrome

ovarian cancer (44 y), CRC and breast cancer in family history

 46581

f

33

BMPR1A (NM_004329.2)

c.1243G > A;p.Glu415Lys

juvenile polyposis syndrome

bladder cancer 32y

 18225

f

12

CDH1 (NM_004360.3)

c.1298A > G;p.Asp433Gly

HDGC

suspected LFS

 45312

f

33

MSH6 (NM_000179.2)

c.3724C > T;p.Arg1242Cys

HNPCC

diffuse gastric cancer (33 y), no HNPCC typical findings in tumor tissue, no CDH1 mutation, suspicious family history

 43219

f

65

POLD1 (NM_002691.3)

c.961G > A;p.Gly321Ser

PPAP

medullary thyroid cancer (64 y), in family: pancreatic and breast cancer

  1. ALL = Acute Lymphoblastic Leukemia, CRC = Colorectal Cancer, FAP = Familial adenomatous polyposis, HBOC = hereditary breast and ovarian cancer, HDGC = hereditary diffuse gastric cancer, HNPCC = hereditary nonpolyposis colorectal cancer, JPS = Juvenile Polyposis Syndrome, LFS = Li-Fraumeni Syndrome, MAP = MUTYH-associated Polyposis, MSS = microsatellite stability, PJS = Peutz-Jeghers Syndrome, PPAP = Polymerase-Proofreading Associated Polyposis, y = years of age, age at first diagnosis, * = termination codon