Lynch Syndrome Panel

Lynch Syndrome Panel

This test is used to diagnose or confirm a diagnosis of Lynch syndrome and to assess risk of Lynch syndrome-related malignancies.

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Lynch Syndrome Panel

Test Summary

 

Lynch Syndrome Panel

Test code: 91461

 

Clinical use

  • Diagnose or confirm a diagnosis of Lynch syndrome
  • Assess risk of Lynch syndrome–related malignancies

Clinical background

Lynch syndrome is an inherited condition typically characterized by early-onset colorectal or endometrial cancer. Depending on which gene is altered, affected individuals have an increased risk for one or more of the following cancer types: colon, rectum, uterus, ovaries, prostate, stomach, small intestine, hepatobiliary tract, urinary tract, brain, skin (sebaceous carcinoma), and pancreas.1–3 Affected individuals also have an increased risk of developing benign sebaceous neoplasms (sebaceous adenomas and keratoacanthomas).2 About 1 in 279 individuals in the general population have Lynch syndrome.4

Lynch syndrome is caused by pathogenic germline variants in 1 of 4 DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) or by deletions involving the EPCAM gene. These variants result in a defective MMR process in which nucleotide mismatches that occur during DNA replication are not repaired. Another feature of most Lynch syndrome–associated cancers is microsatellite instability (MSI), which is characterized by insertions or deletions of nucleotides within short repetitive DNA sequences known as microsatellites. An estimated 15% to 41% of Lynch syndrome–associated variants occur in MLH1, 20% to 40% in MSH2, 12% to 35% in MSH6, and 5% to 25% in PMS2.2,5,6 Additionally, deletions in the EPCAM gene, which is immediately upstream from the MSH2 gene, can influence MSH2 gene expression. Deletions within EPCAM occur in <10% of Lynch syndrome cases.2,7

Guidelines recommend tumor screening for Lynch syndrome in all previously untested patients with a history of CRC or endometrial cancer, regardless of age at diagnosis.3,7 Two tumor screening tests are available to detect MMR deficiency, which may be related to Lynch syndrome: (1) analysis for MSI and (2) immunohistochemistry (IHC) analysis for MLH1, MSH2, MSH6, and PMS2 protein expression. Additional tumor screening tests for BRAF variant(s) and MLH1 hypermethylation may also help distinguish sporadic (nonheritable) cancer from Lynch syndrome–associated cancer.3

Guidelines recommend germline testing, performed on blood specimens, for molecular MMR-related genetic variants if MMR deficiency is detected by IHC (ie, if ≥1 specific MMR proteins are absent) or suspected based on a personal or family history of a Lynch syndrome–related cancer.3,7 Targeted testing for a specific Lynch syndrome–associated variant can be based on the IHC results or used when the familial variant is known. Germline testing can be used as the initial test when tumor tissue is insufficient, unsuitable, or unavailable.3,7

Panel-based testing of genes associated with Lynch syndrome may be appropriate for individuals if the familial variant has not yet been identified and they meet at least 1 of the following 3 criteria3:

  1. 1. Have a current or prior diagnosis of Lynch syndrome–related cancer and meet at least 1 of the following criteria
    1. Younger than 50 years at the time of diagnosis or have a synchronous or metachronous Lynch syndrome–related cancer
    2. Have 1 or more first- or second-degree relatives with Lynch syndrome–related cancers diagnosed younger than 50
    3. Have 2 or more first- or second-degree relatives with Lynch syndrome–related cancers diagnosed at any age
    4. Have an untested colorectal tumor with MSI-high characteristics such as a medullary growth pattern, signet ring or mucinous features, tumor infiltrating lymphocytes, and/or a Crohn's-like lymphocytic reaction
  2. 2. Are unaffected but have a family history of at least 1 of the following
    1. One or more first-degree relatives with CRC or endometrial cancer who were either (1) younger than 50 years at the time of diagnosis or (2) had a synchronous or metachronous Lynch syndrome–related cancer
    2. Two or more first- or second-degree relatives with a Lynch syndrome–related cancer (including 1 diagnosed at younger than 50 years)
    3. Three or more first- or second-degree relatives with a Lynch syndrome–related cancer diagnosed at any age
  3. 3. Have ≥5% risk for Lynch syndrome based on computer models (MMRPro, PREMM5, or MMRpredict) or ≥2.5% risk and clinical judgment

The Lynch Syndrome Panel (test code 91461) identifies germline single-nucleotide variants, deletions, and duplications in the genes most commonly associated with Lynch syndrome: MLH1, MSH2, MSH6, PMS2, and EPCAM. Knowledge of variant status in individuals with CRC and asymptomatic family members can aid in patient management, which may minimize cancer burden and thus improve overall outcomes. For example, colonoscopy surveillance in patients with Lynch syndrome can reduce CRC mortality and is recommended every 1 to 2 years beginning as early as age 20 to 25 years or 2 to 5 years before the earliest age at time of diagnosis in the family.3

Gene-specific test codes are available for use when IHC shows loss of expression for one or more of the MMR proteins. A site-specific test code is available for when the familial MMR gene variant is known. Larger panels that include additional genes that have been associated with similar or overlapping cancer risks are also available.

Individuals suitable for testing

  • Individuals with Lynch syndrome–related cancer who meet the criteria listed above for panel-based testing
  • Individuals who have at least 1 of the following
    • An MSI-high test result and normal IHC results
    • Certain abnormal IHC results such as loss of multiple MMR proteins
    • No tumor block tissue available (or insufficient or unusable tissue remaining) for MSI or IHC testing
  • At-risk individuals with unknown familial MMR gene variant

Method

  • Exon capture and amplification, followed by next-generation (massively parallel) DNA sequencing
  • Detects (1) substitutions, small insertions and deletions, and copy number variants in all coding exons and flanking regions, (2) known disease-causing variants in noncoding regions

Interpretive information

A positive result indicates the presence of a pathogenic or likely pathogenic variant in the gene specified and is diagnostic for Lynch syndrome.

A negative result indicates absence of a single nucleotide variant or deletion/duplication in the specified gene and means Lynch syndrome is unlikely. However, failure to identify a pathogenic variant does not rule out a diagnosis of Lynch syndrome or a different inherited cancer syndrome and may prompt consideration of additional germline testing.

A “variant of uncertain clinical significance” (VUS) result indicates that the variant has not been previously described in the literature or that the clinical significance is unclear based upon currently available evidence. Medical management decisions should be based on personal and family history. Family studies may help to learn more about the clinical significance of this variant.

The classification and interpretation of the variant(s) identified reflect the current state of Quest’s understanding at the time of this report. Variant classification and interpretation are subject to professional judgment and may change for a variety of reasons including, but not limited to, updates in classification guidelines and availability of additional scientific and clinical information.

It is important to check in with the laboratory annually for variant updates because new information regarding the variant and classification may become available over time.

Additional assistance in test selection and interpretation of results is available from our Genomic Science Specialists by calling Genomic Client Services at 1.866.GENE.INFO (1.866.436.3463).

References

  1. Dominguez-Valentin M, Sampson JR, Seppälä TT, et al. Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database. Genet Med. 2020;22(1):15-25. doi:10.1038/s41436-019-0596-9
  2. Idos G, Valle L. Lynch Syndrome. In: Adam MP, Mirzaa GM, Pagan RA, eds. GeneReviews® [Internet]. 1993-2023. Accessed June 8, 2023. https://www.ncbi.nlm.nih.gov/books/NBK1211/pdf/Bookshelf_NBK1211.pdf
  3. National Comprehensive Cancer Network® Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Genetic/familial high-risk assessment: colorectal version1.2023. Updated May 30, 2023. Accessed June 8, 2023. http://www.nccn.org
  4. Win AK, Jenkins MA, Dowty JG, et al. Prevalence and penetrance of major genes and polygenes for colorectal cancer. Cancer Epidemiol Biomarkers Prev. 2017;26(3):404-412. doi:10.1158/1055-9965.epi-16-0693
  5. Moreira L, Balaguer F, Lindor N, et al. Identification of Lynch syndrome among patients with colorectal cancer. JAMA. 2012;308(15):1555-1565. doi:10.1001/jama.2012.13088
  6. Peltomäki P, Nyström M, Mecklin JP, et al. Lynch syndrome genetics and clinical implications. Gastroenterology. 2023;164(5):783-799. doi:10.1053/j.gastro.2022.08.058
  7. Giardiello FM, Allen JI, Axilbund JE, et al. Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-Society Task Force on Colorectal Cancer. Am J Gastroenterol. 2014;109(8):1159-1179. doi:10.1038/ajg.2014.186
     

Content reviewed 08/2023

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This test is used to diagnose or confirm a diagnosis of Lynch syndrome and to assess risk of Lynch syndrome-related malignancies.

Test Guide List

Lynch Syndrome Panel

Test Summary

 

Lynch Syndrome Panel

Test code: 91461

 

Clinical use

  • Diagnose or confirm a diagnosis of Lynch syndrome
  • Assess risk of Lynch syndrome–related malignancies

Clinical background

Lynch syndrome is an inherited condition typically characterized by early-onset colorectal or endometrial cancer. Depending on which gene is altered, affected individuals have an increased risk for one or more of the following cancer types: colon, rectum, uterus, ovaries, prostate, stomach, small intestine, hepatobiliary tract, urinary tract, brain, skin (sebaceous carcinoma), and pancreas.1–3 Affected individuals also have an increased risk of developing benign sebaceous neoplasms (sebaceous adenomas and keratoacanthomas).2 About 1 in 279 individuals in the general population have Lynch syndrome.4

Lynch syndrome is caused by pathogenic germline variants in 1 of 4 DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) or by deletions involving the EPCAM gene. These variants result in a defective MMR process in which nucleotide mismatches that occur during DNA replication are not repaired. Another feature of most Lynch syndrome–associated cancers is microsatellite instability (MSI), which is characterized by insertions or deletions of nucleotides within short repetitive DNA sequences known as microsatellites. An estimated 15% to 41% of Lynch syndrome–associated variants occur in MLH1, 20% to 40% in MSH2, 12% to 35% in MSH6, and 5% to 25% in PMS2.2,5,6 Additionally, deletions in the EPCAM gene, which is immediately upstream from the MSH2 gene, can influence MSH2 gene expression. Deletions within EPCAM occur in <10% of Lynch syndrome cases.2,7

Guidelines recommend tumor screening for Lynch syndrome in all previously untested patients with a history of CRC or endometrial cancer, regardless of age at diagnosis.3,7 Two tumor screening tests are available to detect MMR deficiency, which may be related to Lynch syndrome: (1) analysis for MSI and (2) immunohistochemistry (IHC) analysis for MLH1, MSH2, MSH6, and PMS2 protein expression. Additional tumor screening tests for BRAF variant(s) and MLH1 hypermethylation may also help distinguish sporadic (nonheritable) cancer from Lynch syndrome–associated cancer.3

Guidelines recommend germline testing, performed on blood specimens, for molecular MMR-related genetic variants if MMR deficiency is detected by IHC (ie, if ≥1 specific MMR proteins are absent) or suspected based on a personal or family history of a Lynch syndrome–related cancer.3,7 Targeted testing for a specific Lynch syndrome–associated variant can be based on the IHC results or used when the familial variant is known. Germline testing can be used as the initial test when tumor tissue is insufficient, unsuitable, or unavailable.3,7

Panel-based testing of genes associated with Lynch syndrome may be appropriate for individuals if the familial variant has not yet been identified and they meet at least 1 of the following 3 criteria3:

  1. 1. Have a current or prior diagnosis of Lynch syndrome–related cancer and meet at least 1 of the following criteria
    1. Younger than 50 years at the time of diagnosis or have a synchronous or metachronous Lynch syndrome–related cancer
    2. Have 1 or more first- or second-degree relatives with Lynch syndrome–related cancers diagnosed younger than 50
    3. Have 2 or more first- or second-degree relatives with Lynch syndrome–related cancers diagnosed at any age
    4. Have an untested colorectal tumor with MSI-high characteristics such as a medullary growth pattern, signet ring or mucinous features, tumor infiltrating lymphocytes, and/or a Crohn's-like lymphocytic reaction
  2. 2. Are unaffected but have a family history of at least 1 of the following
    1. One or more first-degree relatives with CRC or endometrial cancer who were either (1) younger than 50 years at the time of diagnosis or (2) had a synchronous or metachronous Lynch syndrome–related cancer
    2. Two or more first- or second-degree relatives with a Lynch syndrome–related cancer (including 1 diagnosed at younger than 50 years)
    3. Three or more first- or second-degree relatives with a Lynch syndrome–related cancer diagnosed at any age
  3. 3. Have ≥5% risk for Lynch syndrome based on computer models (MMRPro, PREMM5, or MMRpredict) or ≥2.5% risk and clinical judgment

The Lynch Syndrome Panel (test code 91461) identifies germline single-nucleotide variants, deletions, and duplications in the genes most commonly associated with Lynch syndrome: MLH1, MSH2, MSH6, PMS2, and EPCAM. Knowledge of variant status in individuals with CRC and asymptomatic family members can aid in patient management, which may minimize cancer burden and thus improve overall outcomes. For example, colonoscopy surveillance in patients with Lynch syndrome can reduce CRC mortality and is recommended every 1 to 2 years beginning as early as age 20 to 25 years or 2 to 5 years before the earliest age at time of diagnosis in the family.3

Gene-specific test codes are available for use when IHC shows loss of expression for one or more of the MMR proteins. A site-specific test code is available for when the familial MMR gene variant is known. Larger panels that include additional genes that have been associated with similar or overlapping cancer risks are also available.

Individuals suitable for testing

  • Individuals with Lynch syndrome–related cancer who meet the criteria listed above for panel-based testing
  • Individuals who have at least 1 of the following
    • An MSI-high test result and normal IHC results
    • Certain abnormal IHC results such as loss of multiple MMR proteins
    • No tumor block tissue available (or insufficient or unusable tissue remaining) for MSI or IHC testing
  • At-risk individuals with unknown familial MMR gene variant

Method

  • Exon capture and amplification, followed by next-generation (massively parallel) DNA sequencing
  • Detects (1) substitutions, small insertions and deletions, and copy number variants in all coding exons and flanking regions, (2) known disease-causing variants in noncoding regions

Interpretive information

A positive result indicates the presence of a pathogenic or likely pathogenic variant in the gene specified and is diagnostic for Lynch syndrome.

A negative result indicates absence of a single nucleotide variant or deletion/duplication in the specified gene and means Lynch syndrome is unlikely. However, failure to identify a pathogenic variant does not rule out a diagnosis of Lynch syndrome or a different inherited cancer syndrome and may prompt consideration of additional germline testing.

A “variant of uncertain clinical significance” (VUS) result indicates that the variant has not been previously described in the literature or that the clinical significance is unclear based upon currently available evidence. Medical management decisions should be based on personal and family history. Family studies may help to learn more about the clinical significance of this variant.

The classification and interpretation of the variant(s) identified reflect the current state of Quest’s understanding at the time of this report. Variant classification and interpretation are subject to professional judgment and may change for a variety of reasons including, but not limited to, updates in classification guidelines and availability of additional scientific and clinical information.

It is important to check in with the laboratory annually for variant updates because new information regarding the variant and classification may become available over time.

Additional assistance in test selection and interpretation of results is available from our Genomic Science Specialists by calling Genomic Client Services at 1.866.GENE.INFO (1.866.436.3463).

References

  1. Dominguez-Valentin M, Sampson JR, Seppälä TT, et al. Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database. Genet Med. 2020;22(1):15-25. doi:10.1038/s41436-019-0596-9
  2. Idos G, Valle L. Lynch Syndrome. In: Adam MP, Mirzaa GM, Pagan RA, eds. GeneReviews® [Internet]. 1993-2023. Accessed June 8, 2023. https://www.ncbi.nlm.nih.gov/books/NBK1211/pdf/Bookshelf_NBK1211.pdf
  3. National Comprehensive Cancer Network® Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Genetic/familial high-risk assessment: colorectal version1.2023. Updated May 30, 2023. Accessed June 8, 2023. http://www.nccn.org
  4. Win AK, Jenkins MA, Dowty JG, et al. Prevalence and penetrance of major genes and polygenes for colorectal cancer. Cancer Epidemiol Biomarkers Prev. 2017;26(3):404-412. doi:10.1158/1055-9965.epi-16-0693
  5. Moreira L, Balaguer F, Lindor N, et al. Identification of Lynch syndrome among patients with colorectal cancer. JAMA. 2012;308(15):1555-1565. doi:10.1001/jama.2012.13088
  6. Peltomäki P, Nyström M, Mecklin JP, et al. Lynch syndrome genetics and clinical implications. Gastroenterology. 2023;164(5):783-799. doi:10.1053/j.gastro.2022.08.058
  7. Giardiello FM, Allen JI, Axilbund JE, et al. Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-Society Task Force on Colorectal Cancer. Am J Gastroenterol. 2014;109(8):1159-1179. doi:10.1038/ajg.2014.186
     

Content reviewed 08/2023

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