Characteristics of the test: (includes 1 gene)
MLH1 (OMIM # 120436) - 19 exons
Basic characteristics of the clinical phenotype:
Lynch syndrome, also known as Hereditary Nonpolyposis Colorectal Cancer (HNPCC; OMIM #120435), is an inherited cancer syndrome which results from germline mutations in DNA mismatch repair (MMR) genes. They are responsible for the correction of small errors, that occur in the DNA nucleotide sequence (mismatches) during DNA replication. Mutations in MMR genes lead to widespread genomic instability, characterized by a reduction or increase in the number of tandemly repeated sequences (microsatellites). The microsatellite instability (MSI) leads to the occurrence of somatic mutations in oncogenes and/or in tumor suppressor genes. As a result, Lynch syndrome is characterized by an early onset and a very high risk of developing cancer, particularly in the right colon, but also in the endometrium, ovaries, stomach, bile ducts, kidneys, bladder, ureter, and the brain.
Lynch syndrome is an autosomal dominant disorder with leading cause - a germline mutations in one of the four MMR genes: MLH1, MSH2, MSH6, and PMS2. Mutations in the MLH1 and MSH2 genes are in 80-90% of all patients with Lynch syndrome and are most often seen in families that strictly meet the Amsterdam I criteria.
Mutations in the MSH6 and PMS2 genes occur in almost all of the remaining patients and are characteristic of families with atypical symptoms for HNPCC, such as extracolonic carcinoma; and occur in patients with a low incidence of MHC. Mutations in another gene, EPCAM, are associated with Lynch syndrome. Germline mutations in this gene lead to inactivation of the nearby MSH2 gene by hypermethylation in approximately 1-3% of patients with Lynch syndrome.
The only described mutation in the EPCAM gene, that directly leads to HNPCC, involves a large deletion (Human Gene Mutation Database; www.insight-group.org). The cumulative risk of developing colon cancer for EPCAM deletions was determined to be 75% by age 70, and 12% for developing endometrial cancer in women.
Indications for Referral/Clinical Significance:
Candidates for this test are all patients who strictly meet the revised Bethesda criteria (persons with carcinoma from families fulfilling the Amsterdam criteria: colorectal or uterine tumor with early onset
(before the age of 50); presence of synchronous, metachronous or other colorectal carcinoma, associated with HNPCC, regardless of the age of onset; CRC with a high degree of microsatellite instability (MSN) in patients under 60 years old; Persons with CRC in at least one first-generation relative of HNPCC-associated tumor, with tumor onset before the age of 50 years old.
Individuals with CRC in at least two first- or second-generation relatives with HNPCC – associated tumor, regardless of the age of onset).
Clinical characteristics of Lynch syndrome, defined by Amsterdam II criteria, include hereditary colorectal (Type I) or extracolonic (Type II) tumor in at least three relatives within at least two consecutive generations, with age of onset before 50 years old in at least one of the relatives, and excluding cases of familial adenomatous polyposis (FAP). The tumor must be histologically verified.
- Enables the identification of a hereditary genetic defect which affects the MMR genes in patients with colorectal cancer in whom the tumor has shown a positive IHH reaction and/or MCH;
- Allows the confirmation of the diagnosis in the presence of a family history with early onset of colorectal cancer and a known deletion/duplication in the family;
- Allows the identification of a predisposition in an asymptomatic family member with a family history of colorectal carcinoma.
Interpretation of results:
The detection of mutations in the MLH1/MSH2 genes allows the diagnosis of Lynch syndrome.
The genetic counselor will interpret and answer all questions about your result.
Method: Sanger sequencing
The method involves bi-directional DNA sequencing of all coding exons and intron-exon boundaries of the MLH1 gene. The laboratory offers a single exon or exon pair sequencing in relatives of patients to determine carrier status in cases where the mutation is known (Tests #182 and 183).
What does the test involve?
· DNA isolation and sample storage.
· Direct sequencing of target genes/gene regions to detect pathogenic mutations.
· Forming a written result of the genetic test.
· Diagnostic interpretation of results and genetic counseling.
Biological material: Fresh or FFPE tumor tissue, or DNA, isolated from Fresh or FFPE tumor tissue. For more information, please read the "Biological material requirements and shipping information" carefully.
