Clinical significance:Pathogenic (Last evaluated: Jan 1, 2012)

Review status:(0/4) 0 stars out of maximum of 4 stars

no assertion criteria provided

Based on:
1 submission [Details]
Record status:

Allele description [Variation Report for MLH1, HYPERMETHYLATION]


MLH1:mutL homolog 1 [Gene - OMIM - HGNC]
Variant type:
Cytogenetic location:
Preferred name:
Other names:
OMIM: 120436.0015


Lynch syndrome II (HNPCC2)
COLON CANCER, FAMILIAL NONPOLYPOSIS, TYPE 2; MLH1-Related Hereditary Non-Polyposis Colon Cancer; MLH1-Related Lynch Syndrome
MedGen: C1333991; Orphanet: 144; OMIM: 609310

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000038907OMIMno assertion criteria providedPathogenic
(Jan 1, 2012)
unknownliterature only

PubMed (3)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownnot providednot providednot providednot providednot providednot providedliterature only



Further evidence for heritability of an epimutation in one of 12 cases with MLH1 promoter methylation in blood cells clinically displaying HNPCC.

Morak M, Schackert HK, Rahner N, Betz B, Ebert M, Walldorf C, Royer-Pokora B, Schulmann K, von Knebel-Doeberitz M, Dietmaier W, Keller G, Kerker B, Leitner G, Holinski-Feder E.

Eur J Hum Genet. 2008 Jul;16(7):804-11. doi: 10.1038/ejhg.2008.25. Epub 2008 Feb 27.

PubMed [citation]
See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000038907.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (3)


Gazzoli et al. (2002) examined 14 cases suspected to represent hereditary nonpolyposis colorectal carcinoma (609310) with microsatellite instability (MSI), but in which no germline MSH2 (609309), MSH6 (600678), or MLH1 mutations were detected, for hypermethylation of CpG sites in the critical promoter region of MLH1. The methylation patterns were determined using methylation-specific PCR and by sequence analysis of sodium bisulfite-treated genomic DNA. In 1 case, DNA hypermethylation of 1 allele was detected in DNA isolated from blood. In the tumor from this case, which showed high microsatellite instability, the unmethylated MLH1 allele was eliminated by loss of heterozygosity, and the methylated allele was retained. This biallelic inactivation resulted in loss of expression of MLH1 in the tumor as confirmed by immunohistochemistry. These results suggested a novel mode of germline inactivation of a cancer susceptibility gene.

Morak et al. (2008) identified hypermethylation of the MLH1 proximal promoter region in peripheral blood cells of 12 (13%) of 94 unrelated patients with tumors and loss of MLH1 protein expression without mutations in the MLH1 gene. Normal colonic tissue, buccal mucosa, and tumor tissue available from 3 patients also showed abnormal methylation at the MLH1 promoter. Seven patients who were heterozygous for informative SNPs showed allele-specific methylation that was not restricted to either allelic variant. Five patients had about 50% methylation, consistent with complete methylation of 1 allele. One patient showed 100% methylation, and the rest showed mosaicism or incomplete methylation. Hypermethylation was found in 1 mother-son pair, suggesting familial predisposition for an epimutation. However, there was no evidence for epigenetic inheritance in the remaining families, and 6 patients showed a mosaic or incomplete methylation pattern, which argued against inheritance. Morak et al. (2008) concluded that MLH1 hypermethylation in normal body cells may constitute a pre-lesion, and that patients with such defects should be under surveillance.

Crepin et al. (2012) identified constitutional MLH1 epimutations in 2 (1.5%) of 134 patients suspected of having Lynch syndrome who did not have germline mutations in the MMR genes. One patient was a man who developed colorectal cancer at age 35 years. Tumor tissue showed MSI, and analysis of lymphocyte DNA showed complete hypermethylation of the promoter of 1 MLH1 allele. The second patient was a woman with colorectal cancer, who had a son with colorectal cancer and 2 daughters with dysplastic colonic polyps. Blood from the mother showed 20% hypermethylation at the MLH1 promoter, suggesting mosaicism. The son and 1 affected daughter also showed partial hypermethylation in blood, suggesting transmission of the epimutation through the germline. Tumor tissue from the 3 patients in the second family also showed partial hypermethylation at MLH1, with loss of MLH1 expression in 2. Finally, tumor tissue from the daughter also carried a somatic BRAF mutation (164757.0001).

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownnot providednot providednot providednot providednot providednot providednot providednot provided

Last Updated: Dec 15, 2017