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Table 1 Rare POLE and POLD1 variants predicted to be deleterious identified in this study

From: Rare germline variants in POLE and POLD1 encoding the catalytic subunits of DNA polymerases ε and δ in glioma families

Patient ID

Gene

Genomic position (GRCh37/hg19)

Nucleotide change

Amino acid change

dbSNPa

MAFb

Prediction according to

CADD scoreg

Previously described in germline of patients with

MutationTasterc

SIFTd

Poly Phen-2e

PROVEANf

Heterozygous POLE and POLD1 germline variants identified in glioma patients from 10 tumor families

Fam011-III.1/M1

POLE

12:133257789

c.139C>T

p.(R47W)

rs143626223

0.001243

DC

D

PrD

Del

27.1

BC [9], CRC [9, 16,17,18], EC [19], OC [9]

Fam011-II.2

WI70-III.1

POLE

12:133253974

c.776G>A

p.(R259H)

rs61732929

0.009734

DC

T

B

N

23.3

BC [9, 20], CRC [9, 20], OC [9]

WI127-III.2

WI161-II.1

POLE

12:133253971

c.779G>A

p.(R260Q)

rs5744752

0.0001242

DC

D

B

Del

23.8

BC [9], CRC [9]

WI207-III.1

POLE

12:133249853

c.1370C>T

p.(T457M)

rs878854842

-

DC

D

PoD

Del

26.1

CRC [21], PTC [22]

WI140-III.1

POLE

12:133235911

c.3245G>A

p.(R1082H)

rs201744227

0.0002486

DC

T

B

Del

25.5

BC [9], CRC [17, 23]

WI69-III.1

POLE

12:133220454

c.4259C>T

p.(A1420V)

rs41561818

0.004536

DC

T

B

N

21.2

BC [9, 24], CC [24], CRC [9, 25], Mel [24], OC [9]

WI104-III.1

POLE

12:133202740

c.6494G>A

p.(R2165H)

rs5745068

0.003258

DC

T

PrD

Del

25.9

BC [9, 24, 26], CC [24], CRC [9, 27], EC [28], Mel [24], OC [9]

WI27-III.1

POLD1

19:50905151

c.433G>A

p.(A145T)

rs137953986

0.002778

DC

T

B

N

20.4

BC [24], CC [24], Mel [24]

WI40-II.1

POLD1

19:50905173

c.455C>T

p.(A152V)

rs41563714

0.001057

DC

T

B

N

20.5

BC [9], CRC [29], Mel [9], OC [9]

Heterozygous POLE variant identified in the glioblastoma of a patient who developed a spinal metastasis

M2h

POLE

12:133201381

c.6763A>T

p.(I2255F)

rs73155056

0.005655

DC

T

B

N

22.3

BC [9], CRC [9], OC [9]

Homozygous POLD1 germline variant identified in an oligodendroglioma patient without family history of cancer

WII-40-II.1

POLD1

19:50918229

c.2546G>A

p.(R849H)

rs3218775

0.008146

DC

T

B

N

22.1

CRC [30]

  1. Given are all identified rare (minor allele frequency, MAF ≤ 0.01), non-silent (i.e. splice site, frameshift, in-frame indels, stop gained/lost and non-synonymous missense) variants predicted to be deleterious by at least one prediction tool, i.e. MutationTaster, SIFT, PolyPhen-2 or PROVEAN, in the POLE or POLD1 gene. NCBI reference sequence NM_006231.4 (POLE) and NM_002691.4 (POLD1). B, benign; BC, breast cancer; CC, cervical cancer; CRC, colorectal cancer; D, damaging; DC, disease causing; Del, deleterious; EC, endometrial cancer; Mel, melanoma; N, neutral; OC, ovarian cancer; PoD, possibly damaging; PTC, papillary thyroid cancer; PrD, probably damaging; T, tolerated
  2. aSNP database ID (https://www.ncbi.nlm.nih.gov/SNP/)
  3. bAccording to the Genome Aggregation Database (gnomAD) browser v2.1.1, controls, non-Finnish European population (https://gnomad.broadinstitute.org)
  4. cAccording to MutationTaster (https://www.mutationtaster.org)
  5. dAccording to SIFT (https://sift.bii.a-star.edu.sg)
  6. eAccording to PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/)
  7. fAccording to PROVEAN (https://www.jcvi.org/research/provean)
  8. gAccording to CADD (https://cadd.gs.washington.edu)
  9. hOnly tumor DNA of the patient was analyzed (non-neoplastic DNA was not available)
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Acta Neuropathologica Communications

ISSN: 2051-5960

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