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Gene test interpretation: Lynch syndrome genes (MLH1, MSH2, MSH6, PMS2, EPCAM)

Gene test interpretation: Lynch syndrome genes (MLH1, MSH2, MSH6, PMS2, EPCAM)
Literature review current through: Jan 2024.
This topic last updated: Aug 08, 2022.

INTRODUCTION — This monograph summarizes the interpretation of germline testing for a Lynch syndrome gene. It does not discuss indications for testing and is not intended to replace clinical judgment in the decision to test or in the clinical care of the individual who was tested. It also does not discuss testing of tumors for DNA mismatch repair (MMR) or microsatellite instability (MSI). These subjects are discussed separately [1]. (See 'UpToDate topics' below.)

OVERVIEW

How to read the report — An approach to reviewing a genetic test report is summarized in the checklist (table 1).

Testing involves two steps: determining the genotype and interpreting the pathogenicity of the variant(s).

Genotype – Identifies the variant(s). Should be repeated in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory, or comparable accreditation body in other jurisdictions, if the results were obtained by direct-to-consumer testing or a research study and would impact clinical care (eg, positive finding; negative finding in an individual with a suspected colorectal cancer syndrome based on personal or family history).

Interpretation – Determines pathogenicity of the variants identified. May require updating. (See 'Classification of variants' below.)

The table provides a glossary of terms in genetic testing reports (table 2).

Classification of variants — It is important to review which gene(s) were analyzed and which variants in those genes were tested, as some tests use comprehensive sequencing whereas others only screen for selected genes and/or selected variants.

The pathogenicity of each variant is classified by the testing laboratory into one of five categories based on information available to them at the time (table 3) [2].

The classification for many variants continues to be updated, especially for variants of uncertain significance (VUS), as more evidence regarding pathogenicity (or lack thereof) becomes available. The uncertainty reflects the current state of information and knowledge available, rather than the accuracy of genotyping or the likelihood of disease.

If there is concern about the classification, such as for a VUS, obtain an updated interpretation periodically (eg, annually). This can be done by checking a database such as ClinVar, contacting the laboratory, or consulting a clinical geneticist, genetic counselor, or other specialist (see 'Locating an expert' below); there is no gold standard approach. Some laboratories routinely provide updates and others require a request. Likely benign and benign variants are typically not reported (or are reported as negative). Many VUSs are reclassified as benign.

Disease associations — DNA mismatch repair (MMR) is a normal component of genome maintenance. Lynch syndrome (previously called hereditary nonpolyposis colorectal cancer [HNPCC]) is a cancer predisposition syndrome caused by a germline mutation that impairs MMR.

Lynch syndrome genes include:

MLH1

MSH2

MSH6

PMS2

EPCAM (gene upstream of MSH2 that affects MSH2 transcription)

Pathogenic and likely pathogenic variants in Lynch syndrome genes are associated with increased risk for several cancers [3]:

Colorectal

Endometrial

Ovarian

Urinary tract (more frequent with pathogenic or likely pathogenic variants in MSH2, especially males)

Gastric and small bowel

Hepatobiliary and pancreatic

Brain (gliomas)

Skin (sebaceous)

Selected cancer risks are summarized in the table (table 4).

Colorectal cancers in individuals with a pathogenic or likely pathogenic variant in a Lynch syndrome gene will have deficient mismatch repair (dMMR) and high levels of microsatellite instability (MSI-H).

Lynch syndrome is autosomal dominant with incomplete penetrance (table 2). A pathogenic variant inherited from one parent is sufficient to increase risk for the associated cancers, but not all individuals with the variant will develop cancer.

Rarely, two pathogenic variants (inherited from both parents) may co-occur, leading to constitutional MMR deficiency (CMMRD), a syndrome of hematologic cancers, brain tumors, Lynch syndrome cancers in childhood, and a neurofibromatosis 1-like phenotype. (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis", section on 'Differential diagnosis'.)

PEOPLE WITHOUT CANCER

Implications of a pathogenic or likely pathogenic variant — Counseling and cancer risk reduction is the same regardless of whether a variant is classified as pathogenic or likely pathogenic. Absence of a family history does not alter the increased risk conferred by such a variant. Discussion should include the range of cancer risks, possible interventions for surveillance or risk reduction, and implications for at-risk family members. The discussion is individualized based on the tested individual's age.

Counseling may require additional visits or referral to a clinical geneticist, genetic counselor, or specialist. Genetic test results are rarely an emergency; most management decisions can be deferred until questions have been answered.

Adherence to the National Comprehensive Cancer Network (NCCN) recommendations for surveillance and risk reduction is generally appropriate [3]. Some features of the family history may warrant additional surveillance (eg, screening at an earlier age, screening for other cancers common to the family).

Several evaluations and interventions are available (table 5). The following represent general recommendations; each individual should meet with a specialist and use shared decision-making to determine their personalized management (algorithm 1).

Colorectal cancer:

Colonoscopy starting at age 20 to 25 years (earlier for some based on family history); repeated every one to two years.

Discussion of aspirin for chemoprevention. Regular use may reduce the long-term incidence of colorectal cancer, but the optimal dose is unknown. The decision is individualized; many will choose to take low-dose aspirin.

Gastric cancer:

Upper endoscopy with visualization of the duodenum starting at age 30 to 35 years; repeated every two to four years.

Helicobacter pylori testing and treatment if positive.

Endometrial and ovarian cancers:

Education regarding symptoms and importance of evaluating them:

-Endometrial cancer symptoms – Abnormal uterine bleeding, postmenopausal bleeding.

-Ovarian cancer symptoms – Pelvic/abdominal pain, bloating, increased abdominal girth, early satiety, urinary changes.

Discussion of risk-reducing surgery:

-Hysterectomy and bilateral salpingo-oophorectomy (BSO) are advised after completion of childbearing.

-Small retrospective series suggest significant risk reduction.

-Risks include perioperative complications and premature menopause in premenopausal women.

Discussion of increased surveillance for those who have not undergone risk-reducing surgery, acknowledging lack of evidence for a reduction in mortality:

-Endometrial biopsies for those who have not undergone hysterectomy.

-Transvaginal ultrasounds and serum CA-125 assays for those who have not undergone BSO.

Surveillance is typically started at age 30 to 35 (or 5 to 10 years prior to the earliest age of endometrial cancer in the family). The optimal frequency of these evaluations is unknown, and the recommended intervals vary by the type of surveillance test being used.

Consideration of hormonal chemoprevention with an oral contraceptive for those who are premenopausal and have not had risk-reducing surgery.

Urothelial cancer:

Consideration of annual urinalysis starting at age 30 to 35, especially for individuals with an MSH2 variant, males, and those with a family history of urothelial cancer.

Skin cancer:

Skin examination every one to three years.

Prostate cancer:

In MSH2 and MSH6 carriers, discussion of prostate cancer screening by prostate-specific antigen test at age 40 and follow-up in a high-risk cancer screening clinic.

Individuals with a strongly positive family history for a particular type of cancer (eg, pancreatic cancer) may choose to undergo more aggressive surveillance. Conversely, it may be appropriate for individuals with a pathogenic variant in a lower risk gene (eg, PMS2) to begin surveillance at later ages or with less frequency.

Details and supporting evidence are presented separately. (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Cancer screening and management" and "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Screening and prevention of endometrial and ovarian cancer" and "Genetic risk factors for prostate cancer", section on 'Lynch syndrome and mismatch repair deficiency' and "Genetic risk factors for prostate cancer", section on 'IMPACT study'.)

Implications of a negative test — Negative testing means that specific pathogenic variants tested were not found (algorithm 1).

If a pathogenic variant has been identified in a family and the tested individual does not have that variant, they can be reassured, with the caveats outlined above (see 'How to read the report' above). For some individuals, risk may be increased by other factors (genetic and/or acquired), and additional testing with a multigene panel may be appropriate.

If a pathogenic variant has not been identified in a family and the tested individual does not have a pathogenic variant, surveillance is based on family history and other risk factors. Referral to a clinical geneticist, oncologist, or genetic counselor may be helpful if there is a strong family history of cancer. (See "Epidemiology and risk factors for colorectal cancer" and 'Locating an expert' below.)

Implications of a VUS — Individuals who have a variant of uncertain significance (VUS) should be managed based on their personal and family history and not the VUS (algorithm 1). Pathogenicity may be revised, and updated information should be sought periodically. (See 'Classification of variants' above.)

PEOPLE WITH CANCER — The implications of genetic testing results should be discussed with the individual's oncologist or surgeon. Referral to a specialist in hereditary colorectal cancer syndromes may be appropriate.

Considerations for a pathogenic or likely pathogenic variant in a Lynch syndrome gene include:

More extensive colorectal cancer surgery.

Prophylactic hysterectomy and risk-reducing bilateral salpingo-oophorectomy (rrBSO) for women at the time of colorectal cancer resection.

Ongoing surveillance for those who have less extensive surgery (eg, annual colonoscopy).

Option of cancer immunotherapy (eg, a programmed cell death-1 [PD-1] inhibitor, with or without a CTLA-4 inhibitor).

Details are presented separately. (See 'UpToDate topics' below.)

Counseling and testing of at-risk family members should be discussed. (See 'Considerations for the family' below.)

For individuals with a negative test or a variant of uncertain significance (VUS) for whom there is concern about a genetic cause, additional genetic testing may be appropriate; this may be discussed with a clinical geneticist, genetic counselor, the primary oncologist, or other specialist. (See 'Implications of a VUS' above.)

CONSIDERATIONS FOR THE FAMILY

Reproductive counseling — Reproductive counseling (ideally done prior to conception) is appropriate for individuals with a pathogenic or likely pathogenic variant who are considering childbearing.

Some may opt for donor gametes or in vitro fertilization (IVF) with preimplantation genetic testing (PGT). (See "Preimplantation genetic testing", section on 'Patients known to be at increased risk of offspring with a specific medically actionable condition'.)

At-risk relatives — Individuals with a pathogenic variant or likely pathogenic variant should discuss this with their at-risk relatives and inform them about the importance of genetic counseling and/or possible testing.

The risk of having inherited the variant is approximately 50 percent for first-degree relatives. Other at-risk relatives may include aunts, uncles, nieces, nephews, and cousins.

Usually the variant segregates on the side of the family with Lynch syndrome cancers; however, if possible, it is recommended to test an affected parent or other relative with a Lynch syndrome cancer to confirm which side of the family is at risk.

Most Lynch syndrome cancers do not develop until adulthood. Deferral of testing until age 18 or older is appropriate to allow informed consent. (See "Genetic testing", section on 'Ethical, legal, and psychosocial issues'.)

RESOURCES

UpToDate topics

Cancer risks – (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Cancer screening and management".)

Testing and diagnosis – (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis".)

Colorectal cancer screening – (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Cancer screening and management", section on 'Screening for Lynch-associated cancers'.)

Endometrial cancer screening – (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Screening and prevention of endometrial and ovarian cancer".)

Cancer risk reduction – (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Cancer screening and management", section on 'Management'.)

Colorectal cancer treatment

General principles – (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Cancer screening and management", section on 'Management'.)

Adjuvant therapy – (See "Adjuvant therapy for resected stage II colon cancer" and "Adjuvant therapy for resected stage III (node-positive) colon cancer".)

Metastatic disease – (See "Systemic therapy for metastatic colorectal cancer: General principles" and "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach".)

Rectal cancer – (See "Overview of the management of rectal adenocarcinoma" and "Neoadjuvant therapy for rectal adenocarcinoma".)

Immunotherapy – (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors".)

Locating an expert

Clinical geneticists – American College of Genetics and Genomics (ACMG)

Genetic counselors – National Society of Genetic Counselors (NSGC)

National Institutes of Health (NIH) Cancer Genetics Services Directory

  1. Supporting references are provided in the associated UpToDate topics, with selected citation(s) below.
  2. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17:405.
  3. https://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf (Accessed on August 22, 2019).
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