Table 1

Clinical features of reported cases with a constitutional MLH1 epimutation

CaseSexPrimary carcinomaAge (years)CriteriaTumour featuresRelevant family historyNotable features of epimutationRef
1FColon25BGMSI, MLH1−, LOHNoneExtensive monoallelic methylation8
H166FColon (Asc)38BGMSI, MLH1−, LOHNoneExtensive methylation9
Endometrium44MSI, MLH1−, ROH
H403MColon (Trans)28BGMSINo FDRsExtensive methylation9
H450FColon (Asc)23BGNANo FDRsExtensive methylation9
H628MColon (Desc)17BGNANo FDRsExtensive methylation9
Colon (Asc)29MSI, MLH1−
VTFCaecum46BGMSI, MLH1−, LOHMother, colon 64 yearsMonoallelic methylation with some mosaicism10
Endometrium53MSI, MLH1−, ROH
Breast (infiltrating duct)63MSI, MLH1−, LOH
TTMCaecum43BGMSI, MLH1−, LOHMother, endometrium 55 yearsMonoallelic methylation with some mosaicism. No methylation in spermatozoa.10, 49
Colon (Desc)44NA
Duodenum (sync)51MSI, MLH1−, LOH
Ampulla of Vater59MSI, MLH1−, LOH
STMColon39BGMSI, MLH1−, LOHNoneExtensive methylation arising de novo on maternal allele. Complete allelic inactivation.11
AFEndometrium45BGMSI, MLH1−No FH. Epimutation transmitted to son (unaffected at age 48 years) in non-Mendelian patternExtensive monoallelic methylation in proband and methylation of maternal allele in son. Complete allelic inactivation in both. No methylation, plus allelic reactivation in spermatozoa of son.12
Colon (Asc)59MSI, MLH1−, L724W*
Rectum,60MSI, MLH1−, S108R*
Skin sarcoma68MSI, MLH1−
BFColon41BGMSI, MLH1−NoneDe novo methylation of maternal allele. Complete allelic inactivation.12
Rectum45MSI, MLH1−
2MEpidermoid (lip)34NANoneDe novo methylation (parental allele NI)13
Colon35BGMSI, MLH1−, LOH
1MColon (Asc)33BGMSI, MLH1−, BRAF WTBrother, gastric 51 yearsExtensive methylation14
Colon (Sig) and rectum47, 47
2FColon (Sig)58BGMSI, MLH1−, BRAF WTSon, hyperplastic polyp 34 yearsExtensive methylation14
Colon (Trans)59MSI, MLH1−, BRAF WT
3MRectum41BGMSI, MLH1−, BRAF WTMother, colon 59 years; brother, polyps 44 yearsSome mosaicism14
4MColon (Trans)39BGMSI, MLH1−, BRAF WTMother unaffected at 64 yearsMaternally inherited, mosaic in mother & proband14
5FRectum40BGMSI, MLH1−Mother, cervical 33 years, colon 64 years (MSS, MLH1+)Extensive monoallelic methylation arising de novo on maternal allele14
Colon (Sig)41
6MColon (Asc)40BGMSI, MLH1−Father, polyps 50 yearsExtensive monoallelic methylation.14
7MColon (Trans)33BGMSI, MLH1−NoneExtensive monoallelic methylation.14
8MColon (Asc)35BGMSI, MLH1−No FDRMosaic. Partial allelic silencing demonstrated.14
Skin42, 48
Cyst, sebaceous gland49
9FColon (Asc)37BGMSI, MLH1−Father, renal 41 yearsDe novo on maternal allele, some mosaicism14
10FColon (left flexure)30BGMSI, MLH1−NoneExtensive monoallelic methylation.14
11MColon (Asc and Trans)46, 46BGMSI, MLH1−NoneSome mosaicism14
12FColon (Asc)35BGMSI, MLH1−, BRAF WTNoneSome mosaicism14
(H10)MColorectal41BGMSI, MLH1−NoneUnconfirmed extensive methylation by MSP46
(H29)FColorectal37Am IMSI, MLH1−Positive FH, unspecifiedUnconfirmed extensive methylation by MSP46
(H32)MColorectal51Am IMSI, MLH1+Positive FH, unspecifiedUnconfirmed partial methylation by MSP46
(H42)MColorectal65Am IMSI, NAPositive FH, unspecifiedUnconfirmed partial methylation by MSP46
(H46)†MColorectal48Am IMSI, MLH1+Positive FH, unspecifiedUnconfirmed partial methylation by MSP46†
N2FColon35BGMSI, MLH1−, ROHExtensive hemiallelic methylation. Complete allelic inactivation.15
F36FColon22, 45MSI, MLH1−Linked 6.4kb deletion from 68bp upstream of ATG start site to intron 2. Complete allelic inactivation.15
  • Am, Amsterdam criteria; Asc, ascending; BG, Bethesda guidelines; C, criterion within specified clinical guidelines; Desc, descending; F, female; FDRs, first degree relatives; FH, family history; IHC, immunohistochemistry; LOH, loss of heterozygosity; M, male; Mod, modified; MSI, microsatellite unstable; MSP, methylation specific; MSS, microsatellite stable; NA, not available for study; Rev, revised; ROH, retention of heterozygosity; Sig, sigmoid; Sync, synchronous; Trans, transverse; WT, wild-type.

  • Clinical, tumour and molecular features are summarised for cases with a constitutional MLH1 epimutation in chronological order as identified. Cases in parentheses are currently unconfirmed.

  • Analyses of tumours for MLH1 expression and the nature of the second hit was not assessed in some cases due to the lack of available specimen.

  • *Unpublished data.

  • †Personal communication with the authors.