Lynch Syndrome Panel, Sequencing and Deletion/Duplication

Last Literature Review: May 2022 Last Update:

To compare directly to other hereditary cancer panels offered by ARUP Laboratories, see the ARUP Hereditary Cancer Panel Comparison table.

  • Recommended test for individuals with a personal and/or family history consistent with Lynch syndrome when documentation of a causative familial variant is not available
  • Testing minors for adult-onset conditions is not recommended; testing will not be performed in minors without prior approval. For additional information, please contact an ARUP genetic counselor at 800-242-2787 ext. 2141.

If a familial sequence variant has been previously identified, targeted sequencing for that variant may be appropriate; refer to the Laboratory Test Directory for additional information.

Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer (HNPCC), is a hereditary cancer syndrome that predisposes individuals to colorectal, endometrial, ovarian, stomach, small bowel, and other cancers. LS is caused by a single pathogenic variant in a mismatch repair (MMR) gene (MLH1, MSH2, MSH6, PMS2) or a pathogenic deletion in the EPCAM gene leading to MSH2 inactivation. Cancer type and risk amount depends on the gene in which the pathogenic variant is located (see Cancer Risk by Gene). Biallelic inheritance of two pathogenic variants in a single MMR gene is consistent with a diagnosis of constitutional mismatch repair deficiency (CMMRD), a rare childhood cancer predisposition syndrome characterized by hematologic, brain, and intestinal tumors.

Disease Overview

Epidemiology

  • LS is the most common hereditary colorectal cancer (CRC) syndrome. 
    • Approximately 2-4% of CRCs are associated with Lynch syndrome. 
  • 1 in 279 individuals from the general population are estimated to have Lynch syndrome. 

Genetics

Genes

See Genes Tested table for genes included in the panel.

Cancer Risk by Gene

Cancer Type Cancer Risk by Age 70 (%)
MLH1 MSH2 MSH6 PMS2 EPCAM

Any

64-78

71-77

28-62

22

Unknown

Colorectum

44-53

42-46

12-20

3

75

Endometrium

35

46

41

13

12

Ovary

11

17

11

3

n/a

Stomach and small bowel

8-16

10-16

2-4

4

n/a

Ureter, kidney

3-4

13-16

2-6

n/a

n/a

Urinary bladder

3-5

7-9

1-4

n/a

n/a

Prostate

7

16

5

5

n/a

Brain

1-2

2-4

1-2

n/a

n/a

Breast (female)

11

13

11

8

n/a

n/a, not available

Source: Idos, 2021 ; Dominguez-Valentin, 2020 

Inheritance

  • LS: autosomal dominant
  • CMMRD: autosomal recessive

Test Interpretation

Methodology

This test is performed using the following sequence of steps:

  • Selected genomic regions, primarily coding exons and exon-intron boundaries, from the targeted genes are isolated from extracted genomic DNA using a probe-based hybrid capture enrichment workflow.
  • Enriched DNA is sequenced by massively parallel sequencing (MPS; also known as next generation sequencing [NGS]) followed by paired-end read alignment and variant calling using a custom bioinformatics pipeline.
  • Sanger sequencing is performed as necessary to fill in regions of low coverage and in certain situations, to confirm variant calls.
  • Long-range PCR followed by nested Sanger sequencing is performed on the following gene and exons:
    • PMS2 (NM_000535) 11, 12, 13, 14, 15
  • Bidirectional Sanger sequencing is performed on the following genes and exons:
    • MSH2 (NM_000251) 5
    • PMS2 (NM_000535) 7
  • Multiplex ligation-dependent probe amplification (MLPA) is performed on the targeted genes to call exon-level deletions and duplications, including the MSH2 10Mb inversion of exons 1-7.

Clinical Sensitivity

  • Variable, dependent on gene 
    • Greater than 80% for the MLH1 and MSH2 genes
    • Unknown for the MSH6 and PMS2 genes
  • Proportion of Lynch syndrome attributed to pathogenic variants in specific MMR gene :
    • MLH1: 15-40%
    • MSH2: 20-40%
    • MSH6: 12-35%
    • PMS2: 5-25%
    • EPCAM: <10%

Analytic Sensitivity

  • For Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) of PMS2: 99%
  • For MLPA of MLH1, MSH2, MSH6 deletions/duplications, and EPCAM exon 9 deletions: 99%
  • For massively parallel sequencing:
Variant Class Analytic Sensitivity (PPA) Estimatea (%) and 95% Credibility Region Analytic Sensitivity (NPA) Estimate (%)

SNVs

>99 (96.9-99.4)

>99.9

Deletions 1-10 bpb

93.8 (84.3-98.2)

>99.9

Insertions 1-10 bpb

94.8 (86.8-98.5)

>99.9

Exon-level deletions/duplications (MLPA)

>99

>99.9

aPPA values are derived from larger methods-based MPS and/or Sanger validations.

bVariants greater than 10 bp may be detected, but the analytic sensitivity may be reduced.

bp, base pairs; NPA, negative percent agreement; PPA, positive percent agreement; SNVs, single nucleotide variants

Contraindications for Ordering

  • Should not be ordered to detect somatic variants associated with malignancy because sensitivity for mosaic variants is low when using the methodology for germline assays
  • Individuals with hematologic malignancy and/or a previous allogenic bone marrow transplant should not undergo molecular genetic testing on peripheral blood specimen.
    • Testing of cultured fibroblasts is required for accurate interpretation of test results.

Results

Result Variant Detected Clinical Significance

Positive

One pathogenic variant detected

Consistent with a diagnosis of Lynch syndrome/hereditary nonpolyposis colorectal cancer (HNPCC)

Negative

No pathogenic variants detected

Diagnosis of Lynch syndrome/hereditary nonpolyposis colorectal cancer (HNPCC), is unlikely but not excluded; does not exclude another hereditary cancer syndrome

Inconclusive

Variant of uncertain clinical significance detected

Uncertain; it is unknown whether variant is benign or pathogenic

Limitations

  • A negative result does not exclude Lynch syndrome or a heritable form of cancer.
  • Diagnostic errors can occur due to rare sequence variations.
  • Interpretation of this test result may be impacted if this individual has had an allogeneic stem cell transplantation.
  • The following will not be evaluated:
    • Variants outside the coding regions and intron-exon boundaries of the targeted genes
    • Regulatory region variants and deep intronic variants
    • Breakpoints of large deletions/duplications
    • Sequence variants in EPCAM
    • Noncoding transcripts
  • The following may not be detected:
    • Deletions/duplications/insertions of any size by massively parallel sequencing
    • Single exon deletions/duplications based on the breakpoints of the rearrangement
    • Low-level somatic variants
    • Single exon deletions/duplications in the following exons:
      • MLH1 (NM_000249) 12
    • Some variants due to technical limitations in the presence of pseudogenes, repetitive, or homologous regions

Genes Tested

To compare directly to other hereditary cancer panels offered by ARUP Laboratories, see the ARUP Hereditary Cancer Panel Comparison table.

Gene MIM Number Disorder/Associated Cancer(s)/Tumor(s) Inheritance

MLH1

120436

 Lynch syndrome/HNPCC

Associated cancer(s)/tumor(s): colorectal, endometrial, stomach, ovarian, small bowel, and others

 AD

CMMRD

 AR

MSH2

609309

Lynch syndrome/HNPCC

Associated cancer(s)/tumor(s): colorectal, endometrial, stomach, ovarian, small bowel, and others

 AD

CMMRD

 AR

MSH6

600678

Lynch syndrome/HNPCC

Associated cancer(s)/tumor(s): colorectal, endometrial, stomach, ovarian, small bowel, and others

 AD

CMMRD

 AR

PMS2

600259

Lynch syndrome/HNPCC

Associated cancer(s)/tumor(s): colorectal, endometrial, stomach, ovarian, small bowel, and others

 AD

CMMRD

 AR
EPCAM

185535

Lynch syndrome/HNPCC

Associated cancer(s)/tumor(s): colorectal and endometrial

 AD

AD, autosomal dominant; AR, autosomal recessive

References

Related Information
Colorectal Cancer - Predictive Testing for Anti-EGFR Therapy
Lynch Syndrome - Hereditary Nonpolyposis Colorectal Cancer (HNPCC)
Lynch Syndrome (HNPCC) Testing Algorithm
Hereditary Cancer Germline Genetic Testing