HNPCC/Lynch Syndrome (MLH1) Sequencing and Deletion/Duplication

Background Information for HNPCC/Lynch Syndrome (MLH1) Sequencing and Deletion/Duplication:
Characteristics: Increased risk of colorectal and extra-colonic cancers including endometrial, renal pelvis, ureter, ovary, stomach, small intestine, and hepatobiliary tract.
Incidence: 1-2 percent of colorectal cancer is due to mismatch repair gene mutations.
Inheritance: Autosomal dominant
Penetrance of MLH1 Mutations: 80 percent lifetime risk of colorectal cancer; 20-60 percent risk for endometrial cancer.
Cause: Pathogenic germline MLH1, MSH2, MSH6, and PMS2 gene mutations.
Gene Tested: MLH1
Clinical Sensitivity: Approximately 45 percent of Lynch syndrome is due to MLH1 mutations.
Methodology: Bidirectional sequencing of MLH1 coding regions and intron-exon boundaries; multiplex ligation-dependent probe amplification (MLPA) to detect large MLH1 exonic deletions.Analytical Sensitivity & Specificity: 99 percent.
Limitations: Diagnostic errors can occur due to rare sequence variations. The breakpoints of large deletions/duplications will not be determined. Regulatory region mutations, deep intronic mutations and mutations in genes other than MLH1 will not be detected. This assay is not designed to detect somatic variants associated with malignancy. Interpretation of this test result may be impacted if the patient has had an allogeneic stem cell transplantation.