Lynch Syndrome Panel, Sequencing and Deletion/Duplication

  • 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
  • When a relative has a previously identified pathogenic sequence variant, see Familial Mutation, Targeted Sequencing (2001961).
Related Tests

Recommended test to confirm a diagnosis of hereditary gastrointestinal (GI) cancer in individuals with a personal or family history of GI cancer and/or polyposis

  • Recommended test if there is a known familial sequence variant previously identified in a family member
  • A copy of the family member’s test result documenting the familial variant is required.

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 Description

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%

Analytical 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 Analytical Sensitivity (PPA) Estimatea (%) Analytical Sensitivity (PPA) 95% Credibility Regiona (%)

SNVs

99.2

96.9-99.4

Deletions 1-10 bp

93.8

84.3-98.2

Deletions 11-44 bp

100

87.8-100

Insertions 1-10 bp

94.8

86.8-98.5

Insertions 11-23 bp

100

62.1-100

aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived.

bp, base pairs; 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.
  • When a relative has a previously identified pathogenic variant, see Familial Mutation, Targeted Sequencing (2001961).

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
    • Certain other variants due to technical limitations in the presence of pseudogenes or repetitive/homologous regions

Genes Tested

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