Table 1

Clinical features of reported cases with a constitutional MLH1 epimutation

Case	Sex	Primary carcinoma	Age (years)	Criteria	Tumour features	Relevant family history	Notable features of epimutation	Ref
1	F	Colon	25	BG	MSI, MLH1−, LOH	None	Extensive monoallelic methylation	8
H166	F	Colon (Asc)	38	BG	MSI, MLH1−, LOH	None	Extensive methylation	9
H166	F	Endometrium	44	BG	MSI, MLH1−, ROH	None	Extensive methylation	9
H403	M	Colon (Trans)	28	BG	MSI	No FDRs	Extensive methylation	9
H450	F	Colon (Asc)	23	BG	NA	No FDRs	Extensive methylation	9
H628	M	Colon (Desc)	17	BG	NA	No FDRs	Extensive methylation	9
H628	M	Colon (Asc)	29	BG	MSI, MLH1−	No FDRs	Extensive methylation	9
VT	F	Caecum	46	BG	MSI, MLH1−, LOH	Mother, colon 64 years	Monoallelic methylation with some mosaicism	10
		Endometrium	53		MSI, MLH1−, ROH
		Melanoma	57		NA
		Breast (infiltrating duct)	63		MSI, MLH1−, LOH
TT	M	Caecum	43	BG	MSI, MLH1−, LOH	Mother, endometrium 55 years	Monoallelic methylation with some mosaicism. No methylation in spermatozoa.	10, 49
		Colon (Desc)	44		NA
		Duodenum (sync)	51		MSI, MLH1−, LOH
		Ampulla of Vater	59		MSI, MLH1−, LOH
ST	M	Colon	39	BG	MSI, MLH1−, LOH	None	Extensive methylation arising de novo on maternal allele. Complete allelic inactivation.	11
A	F	Endometrium	45	BG	MSI, MLH1−	No FH. Epimutation transmitted to son (unaffected at age 48 years) in non-Mendelian pattern	Extensive 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)	59		MSI, MLH1−, L724W*
		Rectum,	60		MSI, MLH1−, S108R*
		Skin sarcoma	68		MSI, MLH1−
B	F	Colon	41	BG	MSI, MLH1−	None	De novo methylation of maternal allele. Complete allelic inactivation.	12
B	F	Rectum	45	BG	MSI, MLH1−	None		12
2	M	Epidermoid (lip)	34		NA	None	De novo methylation (parental allele NI)	13
		Colon	35	BG	MSI, MLH1−, LOH
1	M	Colon (Asc)	33	BG	MSI, MLH1−, BRAF WT	Brother, gastric 51 years	Extensive methylation	14
1	M	Colon (Sig) and rectum	47, 47	BG	MSI, MLH1−, BRAF WT	Brother, gastric 51 years	Extensive methylation	14
2	F	Colon (Sig)	58	BG	MSI, MLH1−, BRAF WT	Son, hyperplastic polyp 34 years	Extensive methylation	14
2	F	Colon (Trans)	59	BG	MSI, MLH1−, BRAF WT	Son, hyperplastic polyp 34 years	Extensive methylation	14
3	M	Rectum	41	BG	MSI, MLH1−, BRAF WT	Mother, colon 59 years; brother, polyps 44 years	Some mosaicism	14
4	M	Colon (Trans)	39	BG	MSI, MLH1−, BRAF WT	Mother unaffected at 64 years	Maternally inherited, mosaic in mother & proband	14
5	F	Rectum	40	BG	MSI, MLH1−	Mother, cervical 33 years, colon 64 years (MSS, MLH1+)	Extensive monoallelic methylation arising de novo on maternal allele	14
5	F	Colon (Sig)	41	BG	MSI, MLH1−	Mother, cervical 33 years, colon 64 years (MSS, MLH1+)		14
6	M	Colon (Asc)	40	BG	MSI, MLH1−	Father, polyps 50 years	Extensive monoallelic methylation.	14
6	M	Rectum	44	BG	MSI, MLH1−	Father, polyps 50 years	Extensive monoallelic methylation.	14
7	M	Colon (Trans)	33	BG	MSI, MLH1−	None	Extensive monoallelic methylation.	14
8	M	Colon (Asc)	35	BG	MSI, MLH1−	No FDR	Mosaic. Partial allelic silencing demonstrated.	14
		Skin	42, 48
		Cyst, sebaceous gland	49
9	F	Colon (Asc)	37	BG	MSI, MLH1−	Father, renal 41 years	De novo on maternal allele, some mosaicism	14
10	F	Colon (left flexure)	30	BG	MSI, MLH1−	None	Extensive monoallelic methylation.	14
11	M	Colon (Asc and Trans)	46, 46	BG	MSI, MLH1−	None	Some mosaicism	14
12	F	Colon (Asc)	35	BG	MSI, MLH1−, BRAF WT	None	Some mosaicism	14
(H10)	M	Colorectal	41	BG	MSI, MLH1−	None	Unconfirmed extensive methylation by MSP	46
(H29)	F	Colorectal	37	Am I	MSI, MLH1−	Positive FH, unspecified	Unconfirmed extensive methylation by MSP	46
(H32)	M	Colorectal	51	Am I	MSI, MLH1+	Positive FH, unspecified	Unconfirmed partial methylation by MSP	46
(H42)	M	Colorectal	65	Am I	MSI, NA	Positive FH, unspecified	Unconfirmed partial methylation by MSP	46
(H46)†	M	Colorectal	48	Am I	MSI, MLH1+	Positive FH, unspecified	Unconfirmed partial methylation by MSP	46†
N2	F	Colon	35	BG	MSI, MLH1−, ROH		Extensive hemiallelic methylation. Complete allelic inactivation.	15
N2	F	Endometrium	45	BG	MSI, MLH1−, ROH			15
F36	F	Colon	22, 45		MSI, MLH1−		Linked 6.4kb deletion from 68bp upstream of ATG start site to intron 2. Complete allelic inactivation.	15
F36	F	Endometrium	40		MSI, MLH1−			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.