Table 2 Rare (population MAF <0.5%) germline variants in MBD4 identified in the patients included in the study.

From: MBD4-associated neoplasia syndrome: screening of cases with suggestive phenotypes

aGermline variant

bPopulation MAF

MAF in studied cohort

cREVEL

Functional effect

Patient (TCGA ID); cancer (age at dx)

dMBD4 somatic 2nd hit

TMB e[# variants analysed]

Tumour mutational signatures

ACMG/AMP variant classification

SBS96 contribution (Cancer Reference Signatures; Signal)

Only SBS1 & SBS96 analysis (Signal)

c.[181T>C];[181T>C]; p.[C61R];[C61R]

0.15%

0.27%

0.044

fNo effect on MBD4 glycosylase activity.

TCGA-D5-6924

CRC (68)

No

4.6 mut/Mb

[137]

SBS96: 58%

SBS1: 100%

Benign: BS2, BS3, BP4, BP5 (mut sig)

c.181T>C; p.(C61R)

0.15%

0.27%

0.044

n.a.

TCGA-AA-3685

CRC (69)

No

1.9 mut/Mb

[59]

SBS96: 64%

SBS1: 100%

c.368C>T; p.(S123L)

0.037%

(0.49% East Asians)

0.09%

0.704

n.a.

TCGA-CA-6718

CRC (46)

gc.1534C>T; p.(R512W)

(REVEL:0.880)

h104 mut/Mb

[3112]

0%

[POLE sig: SBS10a (93%)]

0%

VUS: BS2, PP3

c.1160C>T; p.(S387L)

0.011%

0.09%

0.115

n.a.

TCGA-D5-6530

CRC (53)

No

i24 mut/Mb

[731]

SBS96: 47%

[MMR def sigs: SBS15 (29%), SBS20 (23%)]

SBS1: 74%

SBS96: 26%

VUS: BP4

c.1400A>G; p.(N467S)

0.16%

0.27%

0.540

fNo effect on MBD4 glycosylase activity.

TCGA-AA-3869

CRC (76)

No

1.8 mut/Mb

[57]

SBS96: 54%

SBS1: 100%

Benign: BS2, BS3

TCGA-AA-3950

CRC (79)

No

3.7 mut/Mb

[110]

SBS96: 32%

SBS1: 100%

TCGA-DM-A28K

CRC (75)

No

3.1 mut/Mb

[92]

SBS96: 69%

SBS1: 82%

Unassigned: 18%

jNM_001276271: c.1678C>G; p.(P560A)

0.004%

0.09%

0.190

n.a.

TCGA-AF-2687

CRC (57)

No

3.1 mut/Mb

[94]

SBS96: 64%

SBS1: 95%

Unassigned: 5%

VUS: BP4

  1. Clinical characteristics of the carriers and tumour molecular features are included in the table.
  2. aReference transcript: ENST00000249910 (NM_003925).
  3. bSource: gnomAD v.2.1.1 non-cancer dataset (access date: July 2022).
  4. cREVEL score range: 0-1. The closer to 1 the score, the higher possibility the variant is damaging. Variants with REVEL scores ≥ 0.644 were considered predicted pathogenic, and <0.290, predicted benign, according to recent ClinGen recommendations [14].
  5. dMBD4 somatic events analysed: mutations, copy number alterations and promoter hypermethylation.
  6. eSNVs obtained from cBioportal and analysed with Signal (FitMS) [16].
  7. fFunctional assays that evaluate the effect of the variants on MBD4 glycosylase activity: Sjolund et al. 2013 [15]; Derrien et al. 2021 [13].
  8. gThe type of nucleotide change and trinucleotide context of MBD4 c.1534C>T (TCG>TTG) perfectly fit the type of mutations that most significantly occur in the presence of polymerase proofreading deficiency, as occurs in this tumour due to the presence of POLE exonuclease mutation hotspot c.857C>G; p.P286R.
  9. hUltramutation caused by somatic POLE pathogenic variant c.857C>G; p.P286R (93% of mutational signature contribution: SBS10a, associated with POLE exonuclease mutations).
  10. iHypermutation caused by MMR deficiency due to somatic MLH1 pathogenic variant c.199 G>T; p.G67R (microsatellite instability, MSI) (51% of mutational signature contribution: SBS15 and SBS20, associated with MMR deficiency).
  11. jIntronic variant in the canonical transcript ENST00000249910: c.1665+13C>G.
  12. Abbreviations: CRC colorectal cancer, dx diagnosis, MAF minor allele frequency, MMR def MMR deficient, mut mutation or mutational, mut/Mb mutations per megabase, n.a. data not available, sig signature, VUS variant of unknown significance.
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