Lynch Syndrome Panel

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy GenesCPT Code Copy CPT Codes
5463 EPCAM 81479,81403 Add to Order
MLH1 81292,81294
MSH2 81295,81297
MSH6 81298,81300
PMS2 81317,81319
Full Panel Price* $540
Test Code Test Copy Genes Total Price CPT Codes Copy CPT Codes
5463 Genes x (5) $540 81292, 81294, 81295, 81297, 81298, 81300, 81317, 81319, 81403, 81479 Add to Order

Pricing Comments

We are happy to accommodate requests for testing single genes in this panel or a subset of these genes. The price will remain the list price. If desired, free reflex testing to remaining genes on panel is available.

This test is also offered via our exome backbone with CNV detection (click here). The exome-based test may be higher priced, but permits reflex to the entire exome or to any other set of clinically relevant genes.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

Turnaround Time

The great majority of tests are completed within 20 days.

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

Lynch syndrome, also known as Hereditary Nonpolyposis Colorectal Cancer (HNPCC), is an inherited cancer syndrome mainly caused by germline pathogenic variants in DNA mismatch repair (MMR) genes. MMR genes encode proteins that repair small sequence errors, or mismatches, during DNA replication. Pathogenic variants in mismatch repair genes can cause widespread genomic instability characterized by the expansion and contraction of short tandem repeat sequences (microsatellites) (Grady and Carethers. 2008. PubMed ID: 18773902). As a result, Lynch syndrome is marked by early onset and a high lifetime risk of cancer, particularly in the right colon but also in the endometrium, ovary, stomach, bile duct, kidney, bladder, ureter, and brain (Jang and Chung. 2010. PubMed ID: 20559516). Clinical hallmarks of Lynch Syndrome, as delineated by the Amsterdam criteria, include heritable colorectal (Type I) or extracolonic (Type II) cancer, present in at least three relatives over at least two consecutive generations, with an onset of cancer before the age of 50 in at least one case, and exclusion of familial adenomatous polyposis (FAP) (Vasen et al. 1999. PubMed ID: 10348829).

Genetics

Lynch syndrome is an autosomal dominant disease mainly caused by germline pathogenic variants in one of four MMR genes: MLH1, MSH2, MSH6, and PMS2 (Peltomäki and Vasen. 2004. PubMed ID: 15528792; Kohlmann and Gruber. 2014. PubMed ID: 20301390). Pathogenic variants in the MLH1 and MSH2 genes account for approximately 80-90% of all Lynch syndrome patients, and most frequently occur in families meeting the stringent Amsterdam criteria. Pathogenic variants in the MSH6 and PMS2 genes account for most of the remaining Lynch patients, and are often found in families with atypical HNPCC symptoms, such extracolonic carcinomas; and have also been found to have a low rate of microsatellite instability.

Pathogenic variants in another gene, EPCAM, which encodes a calcium-independent cell adhesion molecule and not a mismatch repair protein, are also involved in Lynch syndrome. Germline pathogenic variants in the EPCAM gene can cause inactivation of the nearby MSH2 gene via hypermethylation in 1-3% of individuals with Lynch syndrome (Kohlmann and Gruber. 2014. PubMed ID: 20301390). The only reported pathogenic variants in the EPCAM gene that are causative for Lynch Syndrome are large deletions (Human Gene Mutation Database; www.insight-group.org). The cumulative incidence of colon cancer risk from EPCAM deletions has been estimated to be 75% by 70 years of age, and for endometrial cancer in women to be 12% (Kempers et al. 2011. PubMed ID: 21145788).

A germline inversion of exons 1-7 in MSH2 has been reported in fourteen individuals from eleven un-related families clinically presenting with Lynch syndrome associated phenotypes including colorectal, endometrial, gastric, and ovarian cancer (Wagner et al. 2002. PubMed ID: 12203789; Rhees et al. 2013. PubMed ID: 24114314; Mork et al. 2016. PubMed ID: 28004223).

See individual gene test descriptions for information on molecular biology of gene products and mutation spectra.

Testing Strategy

For this Next Generation Sequencing (NGS) test, sequencing is accomplished by capturing specific regions with an optimized solution-based hybridization kit, followed by massively parallel sequencing of the captured DNA fragments.

For Sanger sequencing, polymerase chain reaction (PCR) is used to amplify targeted regions. After purification of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit. PCR products are resolved by electrophoresis on an ABI 3730xl capillary sequencer. In nearly all cases, cycle sequencing is performed separately in both the forward and reverse directions.

Copy number variants (CNVs) are also detected from NGS data. We utilize a CNV calling algorithm that compares mean read depth and distribution for each target in the test sample against multiple matched controls. Neighboring target read depth and distribution and zygosity of any variants within each target region are used to reinforce CNV calls. All CNVs are confirmed using another technology such as aCGH, MLPA, or PCR before they are reported.

This panel typically provides ≥98% coverage of all coding exons of the genes listed, plus ~10 bases of flanking noncoding DNA. We define coverage as ≥20X NGS reads or Sanger sequencing.

This test also includes analysis of the inversion of exons 1-7 in MSH2.

Clinical Sensitivity - Sequencing and CNV

Lynch syndrome is attributed to pathogenic sequence variants in the MLH1, MSH2, MSH6, and PMS2 genes in approximately 50%, 40%, 7-10% and <5% of cases, respectively (Kohlmann and Gruber. 2014. PubMed ID: 20301390). The majority of these variants are single nucleotide substitutions or small insertions and deletions. Missense, nonsense and splicing EPCAM pathogenic variants are involved in congenital tufting enteropathy (Human Gene Mutation Database), while EPCAM deletions account for 1-3% of Lynch syndrome cases (Kohlmann and Gruber. 2014. PubMed ID: 20301390). Large deletions and genetic rearrangements account for 20%, 5%, 20%, 7%, and 100% of identifiable pathogenic variants in the MSH2, MLH1, PMS2, MSH6, and EPCAM genes (Kohlmann and Gruber. 2014. PubMed ID: 20301390).

Indications for Test

This test is suitable for individuals with multifocal, recurrent, and early onset (< 50 years) colorectal tumors or a family history of colorectal tumors. Germline pathogenic variants in the Lynch syndrome genes have also been shown to be associated with ovarian cancer (Watson et al. 2008. PubMed ID: 18398828). This test is specifically designed for heritable germline mutations and is not appropriate for the detection of somatic mutations in tumor tissue.

Genes

Official Gene Symbol OMIM ID
EPCAM 185535
MLH1 120436
MSH2 609309
MSH6 600678
PMS2 600259
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Test

Name
PGxome®

Citations

  • Grady and Carethers. 2008. PubMed ID: 18773902
  • Human Gene Mutation Database (Bio-base).
  • Jang and Chung. 2010. PubMed ID: 20559516
  • Kempers et al. 2011. PubMed ID: 21145788
  • Kohlmann and Gruber. 2014. PubMed ID: 20301390
  • Mork et al. 2016. PubMed ID: 28004223
  • Peltomäki and Vasen. 2004. PubMed ID: 15528792
  • Rhees et al. 2013. PubMed ID: 24114314
  • Vasen et al. 1999. PubMed ID: 10348829
  • Wagner et al. 2002. PubMed ID: 12203789
  • Watson et al. 2008. PubMed ID: 18398828
  • www.insight-group.org

Ordering/Specimens

Ordering Options

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

Specimen Types

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