Table 3 Variants of unknown clinical significance identified in a Norwegian breast and ovarian cancer cohort.

From: Identifying sequence variants contributing to hereditary breast and ovarian cancer in BRCA1 and BRCA2 negative breast and ovarian cancer patients

Gene

Variant

Local.

Protein change

Databases

Pr. Ref.

Patient

Diagn. & age

dbSNP

gnomAD

ClinVar

HGMDp

ATM

c.1727T>C

Exon 11

p.(Ile576Thr)

rs730881342

ALL: 0.01%; NFE: 0.01%; FIN: 0.04%

RCV000159685.6; VUS

—

72

P-97

BC, 50y

ATM

c.1986T>C

Exon 13

p.(=)

rs1800055

ALL: 0.05%; NFE: 0.08%; FIN: 0.08%

RCV000123724.5; Likely benign

—

72

P-99

BC, 52y

ATM

c.2164T>C

Exon 14

p.(=)

—

—

—

—

—

P-78

BC, 49y

ATM

c.2220A>C

Exon 14

p.(=)

—

—

—

—

—

P-56

BC, 61y

ATM

c.2804C>T

Exon 19

p.(Thr935Met)

rs3218708

ALL: 0.01%; NFE: 0.01%; FIN: 0%

RCV000131651.8; Likely benign/VUS

CM177861; CRC: DM?

73

P-53

BC, 38y

ATM

c.3549T>C

Exon 24

p.(=)

rs767377764

ALL: 0.00%, NFE: 0%; FIN: 0%

RCV000223274.2; Likely benign

—

—

P-88

BC, 48y

ATM

c.3703C>T

Exon 25

p.(Pro1235Ser)

rs779095853

ALL: 0.00%, NFE: 0.00%; FIN: 0%

RCV000567940.1; VUS

—

—

P-80

BC, 58y

ATM

c.4324T>C

Exon 30

p.(Tyr1442His)

rs201666889

ALL: 0.03%; NFE: 0.06%; FIN: 0.02%

RCV000115190.8; Benign/VUS

CM0910502; BC: DM?

30

P-75

BC, 49y

ATM

c.5229A>G

Exon 36

p.(=)

—

—

RCV000233826.2; Likely benigna

—

—

P-42

BC, 63y

ATM

c.8734A>G

Exon 61

p.(Arg2912Gly)

rs376676328

ALL: 0.02%; NFE: 0.04%; FIN: 0.00%

RCV000131723.10; VUS

CM014034; BC: DM

74

P-14

BC, 35y

BRIP1

c.2087C>T

Exon 14

p.(Pro696Leu)

rs147755155

ALL: 0.00%; NFE: 0.01%; FIN: 0.00%

RCV000116135.9; VUS

—

—

P-31; P-32

OC, 47y; OC, 52y

CDH1

c.136C>G

Exon 2

p.(Leu46Val)

—

—

—

—

—

P-12

OC, 27y

CHEK2

c.470T>C

exon 4

p.(Ile157Thr)

rs17879961

ALL: 0.49%; NFE: 0.53%; FIN: 2.50%

RCV000116018.12; Likely pathogenic /Pathogenic

CM993368; LFS, IR: DFP

75

P-59

BC, 58y

CHEK2

c.538C>T

Exon 4

p.(Arg180Cys)

rs77130927

ALL: 0.09%; NFE: 0.12%; FIN: 0.03%

RCV000116024.8; Benign/VUS

CM030417; PC: DM

76

P-66

BC, 53y

CHEK2

c.1205_1206delinsTC

Exon 11

p.(Ala402Val)

—

—

RCV000537997.1; VUSe

—

—

P-74

BC, 54y

FANCF

c.1087C>T

Exon 1

p.(Gln363*)

rs201285915

ALL: 0.01%; NFE: 0.01%; FIN: 0%

RCV000482395.1; VUSb

CM1824108; BOC: DM

20

P-48

BC, 39y

MLH1

c.1665T>C

Exon 14

p.(=)

rs749204990

ALL: 0.00%, NFE: 0.00%; FIN: 0%

RCV000167487.2; Likely benign

—

—

P-65

BC bilateral, 51y

MSH2

c.1667T>C

Exon 11

p.(Leu556Ser)

rs587779101

—

RCV000076234.2; VUSc

CM148293; LS: DM?

77

P-73

BC, 50y

MSH2

c.2503A>C

Exon 15

p.(Asn835His)

rs41295296

ALL: 0.00%; NFE: 0.01%; FIN: 0%

RCV000115519.10; Likely benign; VUS

—

78

P-82

BC, 37

MSH6

c.3259C>T

Exon 5

p.(Pro1087Ser)

rs63750998

ALL: 0.01%; NFE: 0.02%; FIN: 0%

RCV000074827.4; VUSc

CM1210418; OC: DM

79

P-81

BC, 64y

NBN

c.643C>T

Exon 6

p.Arg215Trp

rs34767364

ALL: 0.25%; NFE: 0.40%; FIN: 0.32%

RCV000115802.12; Benign/Likely benign/ VUS

CM044022; CRC: DM

80

P-75

BC, 49y

NF1

c.378A>G

Exon 4

p.(=)

—

—

——

—

—

P-44

BC, 49y

NF1

c.469A>G

Exon 4

p.(Ile157Val)

—

—

RCV000566319.1; VUS

—

—

P-91

BC, 54y

NF1

c.587-6_587-5delTT

Intron 5

p.(?)

—

—

—

—

—

P-15

BC bilateral, 74/80y

NF1

c.960T>A

Exon 9

p.(=)

rs376447070

ALL: 0.02%; NFE: 0.01%; FIN: 0.17%

RCV000167230.1; likely benign

—

—

P-64

BC, 35y

NF1

c.4926A>G

Exon 37

p.(=)

—

—

—

—

—

P-88

BC, 48y

NF1

c.5225A>G

Exon 37

p.(Asn1742Ser)

rs745407845

ALL: 0.00; NFE: 0.00%; FIN: 0%

RCV000206576.4; VUSd

CM1512958; NF1: DM

81

P-2

BC, 57y

NF1

c.5793T>C

Exon 39

p.(=)

rs779114598

ALL: 0.00%; NFE: 0.01%; FIN: 0%

RCV000167490.1; likely benign

—

82

P-22

BC, 86y

NF1

c.7354C>T

Exon 50

p.(Arg2452Cys)

rs377662483

ALL: 0.00; NFE: 0%; FIN: 0%

RCV000203720.5; VUSd

—

—

P-1

BC, 36

NF1

c.7595C>T

Exon 51

p.(Ala2532Val)

rs148154172

ALL: 0.07%; NFE: 0.05%; FIN: 0.00%

RCV000130730.3; Likely benign

—

—

p-89

BC, 47y

PMS2

c.1765G>C

Exon 11

p.(Asp589His)

rs749727182

ALL: 0.00%; NFE: 0.00%; FIN: 0%

RCV000483031.2; VUSb

—

—

P-49

BC, 41y

PMS2

c.1936A>C

Exon 11

p.(=)

rs369582237

ALL: 0.00%; NFE: 0.01%; FIN: 0%

RCV000163542.2; likely benign

—

—

P-67

BC, 51y

  1. Variants are named according to Human Genome Variation Society (HGVS) nomenclature. Local.: localization; Pr.Ref: Primary reference; diagn.: diagnosis; NFE: Non-Finnish Europeans; FIN: Finnish Europeans; DM: Disease mutation; CRC: colorectal cancer BC: Breast cancer; BOC: Breast and ovarian cancer syndrome; PC: Prostate cancer; CRC: Colorectal cancer; LS: Lynch syndrome; OC: Ovarian cancer; NF1: Neurofibromatosis, type 1; LFS,IR: Li-Fraumeni Syndrome, increased risk; DFP: Disease associated functional polymorphism; y: years. P-75 has two VUS’s, one in ATM and one in NBN. The two MLH1 variants are listed together since they only have been identified in cis in Norway. The ClinVar references and the corresponding clinical significance are mainly linked to the condition “Hereditary cancer-predisposing syndrome”, exceptions are marked.
  2. aAtaxia telangiectasia.
  3. bAllHighlyPenetrant.
  4. cLynch syndrome reviewed by expert panel (InSiGHT).
  5. dNeurofibromatosis, type 1.
  6. eFamilieal cancer of breast.
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