MLH1, EPIGENETICALLY SILENCED INHERITED AND Lynch syndrome II

Clinical significance:Pathogenic (Last evaluated: May 1, 2013)

Review status:(1/4)1 star out of maximum of 4 stars

classified by single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000018636.26

Allele description [Variation Report for MLH1, EPIGENETICALLY SILENCED INHERITED]

Gene:
MLH1:mutL homolog 1 [Gene - OMIM]
Variant type:
Variation
Cytogenetic location:
3p21.3
Other names:
MLH1, EPIGENETICALLY SILENCED INHERITED
Links:
OMIM: 120436.0026

Condition(s)

Name:
Lynch syndrome II (HNPCC2)
Synonyms:
COLON CANCER, FAMILIAL NONPOLYPOSIS, TYPE 2; Lynch Syndrome; Lynch syndrome I; See all synonyms [MedGen]
Identifiers:
MedGen: C1333991; OMIM: 609310; Orphanet: 144
Age of onset:
Adulthood

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Assertion and evidence details

Submission AccessionSubmitterReview StatusClinical Significance
(Last evaluated)
OriginMethodConsequenceCitations
SCV000038919OMIMPathogenic
(May 1, 2013)
germlineliterature only

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

EthnicityOriginAffectedAlleles observedFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only

Citations

PubMed

Inheritance of a cancer-associated MLH1 germ-line epimutation.

Hitchins MP, Wong JJ, Suthers G, Suter CM, Martin DI, Hawkins NJ, Ward RL.

N Engl J Med. 2007 Feb 15;356(7):697-705.

PubMed [citation]
PMID:
17301300

Details of each submission

From OMIM, SCV000038919.1

#EthnicityAlleles ObservedChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)

Description

Hitchins et al. (2007) described a family in which a 66-year-old woman, the mother of 3 sons by 2 different mates, had the clinical picture of hereditary nonpolyposis colorectal cancer. She had metachronous carcinomas that had microsatellite instability and lacked MLH1 expression. The diagnosis of cancer of the endometrium was made at the age of 45; of the colon, at age 59; and of the rectum at 60 years. She was heterozygous for a SNP within the MLH1 promoter (rs1800734), with methylation confined to the A allele. In this woman methylation of the A allele on approximately 50% of chromosomes was confirmed by sulfite sequencing. Hitchins et al. (2007) identified an expressible C-T SNP within MLH1 exon 16 in her son, which was used to demonstrate that he was transcribing RNA only from the MLH1 allele inherited from his father. The data were consistent with transmission of the MLH1 epimutation from the proband to her son. In DNA from peripheral blood leukocytes obtained from this son, approximately half of the MLH1 alleles were methylated. In contrast, his sperm had no trace of MLH1 methylation, despite containing equal proportions of alleles derived from his father and mother. Furthermore, analysis of the RNA in his sperm at the MLH1 exon 16 C-T SNP showed reactivation of the maternally derived MLH1 allele. These results indicated reversion of the MLH1 epimutation to normality during spermatogenesis, suggesting a negligible risk of transmission from that family member.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodVariant allelesAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jul 22, 2014

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