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Condition Description Detection 
Indications
 Specimen Requirements

 

Condition Description

Lynch syndrome, caused by a germline mutation in a mismatch repair gene or associated with tumors exhibiting MSI, is characterized by an increased risk of colon cancer and other cancers (e.g., of the endometrium, ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, skin). Individuals with Lynch syndrome have an approximately 80% lifetime risk for colon cancer. The average age of colorectal cancer diagnosis is 61 years. Women with Lynch syndrome have a 20%-60% lifetime risk of endometrial cancer. The average age of diagnosis of endometrial cancer is age 46-62 years. Among women with Lynch syndrome who develop both colon cancer and endometrial cancer, approximately 50% present first with endometrial cancer. In Lynch syndrome, the mean age of diagnosis of gastric cancer is age 56 years, with intestinal-type adenocarcinoma being the most commonly reported pathology. Lynch syndrome-associated ovarian cancers have a mean age of diagnosis of 42.5 years; approximately 30%are diagnosed before age 40 years.

Lynch syndrome is known to be associated with mutations in four genes involved in the mismatch repair pathway (MLH1, MSH2, MSH6, and PMS2). Germline mutations in MLH1 and MSH2 account for approximately 90% of detected mutations in families with Lynch syndrome. Mutations in MSH6 have been reported in approximately 7%-10% of families with Lynch syndrome. Mutations in PMS2 account for fewer than 5% of mutations in families with Lynch syndrome. Up to 39% of families with mutations in an Lynch syndrome gene do not meet the Amsterdam Criteria. Therefore, families found to have a deleterious mutation in an Lynch syndrome gene should be considered to have Lynch syndrome regardless of the extent of the familyhistory At least 20% of mutations in MSH2 and 5% of mutations in MLH1 are large deletions or genetic rearrangements

Lynch syndrome is inherited in an autosomal dominant manner. The majority of individuals diagnosed with Lynch syndrome have inherited the condition from a parent. However, because of incomplete penetrance, variable age of cancer development, cancer risk reduction as a result of screening or prophylactic surgery, or early death, not all individuals with a Lynch syndrome gene mutation have a parent who had cancer.

Genes

MLH1, MSH2,MSH6

Indications

This test is indicated for:

  •  Confirmation of a clinical diagnosis of Lynch syndrome
  • Individuals at-risk for Lynch syndrome due to family history

Methodology

PCR amplification of 45 exons contained in the MLH1, MSH2, and MSH6 genes is performed on the patient's genomic DNA. Direct sequencing of amplification products is performed in both forward and reverse directions, using automated fluorescence dideoxy sequencing methods. The patient's gene sequences are then compared to a normal reference sequence. Sequence variations are classified as mutations, benign variants unrelated to disease, or variations of unknown clinical significance. Variants of unknown clinical significance may require further studies of the patient and/or family members. This assay does not interrogate the promoter region, deep intronic regions, or other regulatory elements, and does not detect large deletions.

Detection

Clinical Sensitivity: Germline mutations in MLH1 and MSH2 account for approximately 90% of detected mutations in families with Lynch syndrome. Mutations in MSH6 have been reported in approximately 7%-10% of families with Lynch syndrome. Mutations in the promoter region, some mutations in the introns and other regulatory element mutations cannot be detected by this analysis. Large deletions will not be detected by this analysis. Results of molecular analysis should be interpreted in the context of the patient's biochemical phenotype.

Analytical Sensitivity: ~99%

Specimen Requirements    

Submit only 1 of the following specimen types

Type: EDTA Whole Blood; Infants (2 years): 3-5 ml; Older Children & Adults: 5-10 ml.

Type: Isolated DNA: In microtainer: (20-30 ug high Quality Genomic DNA, shipped at 2-4 oC). Isolation using the QiagenTM  Puregene kit for DNA extraction is recommended.

Specimen Collection and Shipping: Refrigerate until time of shipment in 100 ng/ul of TE buffer. Ship sample at room temperature with overnight delivery.