This test analyzes 5 genes associated with a hereditary predisposition to Lynch syndrome (also known as hereditary non-polyposis colorectal cancer [HNPCC]). This tumor predisposition syndrome is characterized by an increased risk of developing colorectal, ovarian, uterine, and other cancers.
Genetic testing of these genes may confirm a diagnosis and help guide treatment and management decisions. Identification of a disease-causing variant would also guide testing and diagnosis of at-risk relatives. This test is specifically designed for heritable germline mutations and is not appropriate for the detection of somatic mutations in tumor tissue.
EPCAM MLH1 MSH2 MSH6 PMS2
EPCAM MLH1 MSH2 MSH6 PMS2
MLH1, MSH2, PMS2, MSH6, and EPCAM can also be ordered as part of a broader panel to test for different types of hereditary cancer, including ovarian, uterine, colon, and pancreatic cancers. Depending on the individual’s clinical and family history, one of these broader panels may be appropriate. Any of these broader panels can be ordered at no additional charge.
Lynch syndrome, also called hereditary non-polyposis colon cancer (HNPCC), increases the risk of many types of cancer, particularly colorectal. Other associated cancers include stomach, small bowel, kidney, central nervous system, biliary tract, pancreatic, prostate and skin. Women with this disorder also have an increased risk for ovarian and uterine cancer. Lynch syndrome is the most common cause of adult-onset hereditary colorectal and uterine cancers.
Colorectal cancer (CRC) is a malignancy of the large intestine (colon) and/or rectum. It is the third-commonest cancer diagnosis in the United States. Although most cases are sporadic and not inherited, approximately 5%-10% of colorectal cancer is hereditary and due to an identifiable pathogenic variant. Up to 5% of all colorectal cancer cases are attributed to Lynch syndrome.
Individuals with Lynch syndrome due to a pathogenic variant in MLH1, MSH2, PMS2, or MSH6 are also carriers of constitutional mismatch-repair deficiency (CMMR-D) syndrome.
Individuals with a pathogenic variant in one of these genes have an increased risk of malignancy compared to the average person, but not everyone with such a variant will actually develop cancer. Further, the same variant can present differently, even among family members. Because we cannot predict which cancers may develop, additional medical management strategies focused on cancer prevention and early detection may benefit most patients who are found to have a pathogenic variant. See table below for gene-associated cancer risks.
|Gene||Colorectal cancer risk||Ovarian cancer risk||Uterine cancer risk||Other associated cancers|
|MLH1||Up to 82%||Up to 20%||14%-54%||GI, urothelial/renal, CNS, biliary tract, glioblastoma, and sebaceous adenoma/carcinoma|
|MSH2||Up to 82%||up to 24%||20%-54%|
|MSH6||20%-44%||6%-8%||Up to 71%|
|PMS2||Up to 20%||Elevated||Up to 15%|
Approximately 5%-10% of colorectal cancer is hereditary and due to an identifiable pathogenic variant. Up to 5% of all colorectal cancer cases are attributed to pathogenic mutations in one of the genes associated with Lynch syndrome.
|Gene||Percentage of Lynch syndrome cases attributed to each gene|
Lynch syndrome is inherited in an autosomal dominant pattern.
Individuals who meet the Amsterdam II Criteria have an established diagnosis of Lynch syndrome, although many affected individuals do not meet these guidelines:
Criteria for evaluating individuals for Lynch syndrome have been established by the National Comprehensive Cancer Network:
The Revised Bethesda Guidelines may also be used to screen individuals with colon cancer for Lynch syndrome:
For management recommendations, please refer to:
Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).
Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.
Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.
|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|
EPCAM: Analysis is limited to deletion/duplication analysis.
MLH1: Deletion/duplication analysis covers the promoter region.
MSH2: Analysis includes the exon 1-7 inversion (Boland mutation).