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FOR THE TESTED INDIVIDUAL – This information is intended to assist your physician or other qualified health care professional as part of their comprehensive assessment of the best approach to managing your genetic test results. It is not specific advice for your care and it does not replace consultation with a qualified health care professional. You should not alter your medical care based on this report without speaking to, and receiving guidance from, your physician based on your specific case.
FOR THE CLINICIAN – This information was prepared on the date indicated on the file and may have been updated subsequently. Please check UpToDate (UpToDate.com) for the latest version of this and other gene test interpretation monographs. UpToDate subscribers can access these monographs by entering the gene name or the phrase "Gene test interpretation" into the UpToDate search box. Your use of this information is subject to the terms set forth at https://www.uptodate.com/legal/license and any other terms in any applicable license agreement. This information is no substitute for individual patient assessment based on the healthcare provider's evaluation of each patient that includes personal and family history, findings from the physical examination, laboratory and other testing, and other factors unique to the patient. The information should be used as a tool to help the clinician reach diagnostic and treatment decisions, bearing in mind that individual and unique circumstances may lead to decisions other than those presented. The opinions expressed are those of the monograph's authors and editors.
Supported by an unrestricted educational grant from AncestryHealth®.
- Daniel C Chung, MD
- Linda H Rodgers, MGC, CGC
- Section Editors:
- Barbara Goff, MD
- Anne Slavotinek, MBBS, PhD
- Deputy Editors:
- Jennifer S Tirnauer, MD
- Shilpa Grover, MD, MPH, AGAF
- Alana Chakrabarti, MD
- Diane MF Savarese, MD
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 . (See 'UpToDate topics' below.)
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 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 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 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:
●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 :
●Urinary tract (more frequent with pathogenic or likely pathogenic variants in MSH2, especially males)
●Gastric and small bowel
●Hepatobiliary and pancreatic
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 . 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).
•Colonoscopy starting at age 20 to 25 years (earlier for some based on family history); repeated every 1 to 2 years.
•Discussion of aspirin for chemoprevention. The benefits, and optimal dose, are unknown. The decision is individualized; many will choose to take low-dose aspirin.
•Upper endoscopy with visualization of the duodenum starting at age 30 to 35 years; repeated every 2 to 3 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.
•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.
•Possible annual skin examination.
Individuals with a strongly positive family history for a particular type of cancer (eg, pancreatic cancer) may choose to undergo more aggressive surveillance.
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".)
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 "Colorectal cancer: Epidemiology, risk factors, and protective factors" 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).
●Consideration of cancer immunotherapy (eg, a programmed cell death-1 [PD-1] 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
Preconception counseling — Preconception counseling 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 'Couples 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'.)
●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 'Cancer screening'.)
●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
•Adjuvant therapy – (See "Adjuvant chemotherapy for resected stage II colon cancer" and "Adjuvant therapy for resected stage III (node-positive) colon cancer".)
•Metastatic disease – (See "Systemic chemotherapy for metastatic colorectal cancer: General principles" and "Systemic chemotherapy for nonoperable metastatic colorectal cancer: Treatment recommendations".)
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
- Supporting references are provided in the associated UpToDate topics, with selected citation(s) below.
- 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.
- https://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf (Accessed on August 22, 2019).
|Section of the report||Action(s)||Concern(s)|
||Individuals may inadvertently provide the wrong name on a test sample. Testing should be done by a laboratory that can ensure that the identification matches the tested individual.|
||All actionable medical testing (eg, positive finding or negative finding in an individual suspected of having a genetic disorder) should be conducted in a CLIA-certified laboratory that has met appropriate quality standards for performing the specific test. Some direct-to-consumer testing is not performed in CLIA-certified laboratories and may lack appropriate quality controls.|
|Date of testing||
||Germline variants do not change over time. However, as new data become available, the classification of variant pathogenicity may change, especially for variants classified as VUS. Repeat testing may be considered, as the technologies for exome sequencing may improve and may identify a variant missed on a prior test.|
||Not all genetic testing panels are comprehensive in the genes or variants in those genes they evaluate. New disease genes or clinically important variants in existing genes may be identified through further research.|
||Not all methods will identify all variants. In some cases such as HFE testing, only one or two variants are clinically relevant, and sequencing of the entire coding region of the gene is not required, whereas in other conditions, limited testing for one or two variants may miss clinically important findings. Gene panels may be especially useful when multiple genes could potentially be responsible for a clinical phenotype.|
|Classification of pathogenicity||
||Interpretation of pathogenicity takes into account many data sources including laboratory research, research databases, population studies, and pedigree analyses. In some cases, pathogenicity is well established (eg, the variant that causes sickle cell disease); in others, it is more subjective and incomplete. Variants classified as VUS, likely benign, or benign generally are not actionable and should not impact medical interventions. Consulting a publicly curated database such as ClinVar or discussing the results with an expert in the specific disease, or referral to a clinical geneticist, genetic counselor, or disease expert may be helpful.|
* Indications for testing vary according to the individual's medical history, family history, and other factors such as desire for preconception counseling. In some cases, an individual who did not have a clinical indication for testing may have an unexpected finding from genetic testing that, if accurate, would indicate the need for an intervention, and such findings may be actionable regardless of the initial reasons for testing.
|Autosomal dominant||Pattern of inheritance that requires only one affected variant allele (a variant inherited from one parent or that arises de novo) to transmit the trait or risk of disease. Not sex-linked. First-degree relatives (siblings, children) have a 50% chance of sharing (or inheriting) the variant allele.|
|Autosomal recessive||Pattern of inheritance that generally requires both variants on both alleles (one from each parent) in order to transmit the trait or risk of disease. Not sex-linked. Individuals with one variant are sometimes called carriers.|
|Carrier||Individual who has a specific variant in one allele of the gene in their germline DNA (inherited from one parent or arising de novo). For recessive disorders, refers to a heterozygote who is generally (or mostly) unaffected. For dominant disorders, carriers are generally considered at risk for the disorder.|
|Expressivity||Differences in the severity of disease manifestations in individuals who share the same genotype (eg, cystic fibrosis is said to have variable expressivity because two individuals with the same genotype may have differences in the degree of pancreatic or lung dysfunction).|
|Genotyping||Determining the DNA sequence of a particular gene or portion of a gene in an individual. Can be done on DNA from sources such as nucleated epithelial cells from saliva, tumor cells from a biopsy, or WBCs from peripheral blood. Can be used to determine germline or somatic sequence, depending on the source of the cells.|
|Germline||Derived from the gametes (sperm or egg cells) and present in the early embryo; germline variants are typically present in all body cells and do not change. Germline variants can be passed down to subsequent generations.|
|Mutation||Term that may be used to describe changes in DNA or protein sequence compared with a reference sequence. The American College of Genetics and Genomics (ACMG) has expressed concern that this term can cause confusion or incorrect assumptions regarding pathogenicity, and the ACMG recommends that findings from genetic testing be described using the term "variant" with a qualifier regarding pathogenicity (or lack thereof).|
|Pathogenicity||Likelihood that a specific variant is capable of causing disease or conferring disease risk. Does not determine the likelihood that disease will occur (which depends on other factors such as disease penetrance). Refer to separate table in UpToDate for the categories.|
|Pedigree||Diagram of a family showing relationships among family members, sex of each family member, presence or absence of one or more genetic disorders, and often the age at which they manifested. Used in genetic counseling to identify possible inherited causes of disease and their inheritance patterns.|
|Penetrance||Likelihood that a person with a disease-associated variant will manifest one or more features of the disease. Many disease variants have incomplete or variable penetrance, meaning that not all individuals with the variant will manifest the associated disorder.|
|Somatic||Referring to tissues that are not within the germline. Variation that arises in somatic tissues is not passed from parent to offspring. Somatic mutations are common in cancer.|
|Variant||Change in the sequence of DNA compared with a reference sequence. Variants can be benign (associated with normal gene function), pathogenic (associated with altered gene function and/or clinical disease, also called mutations), or somewhere in between. The term polymorphism is often (but not exclusively) used for benign variants. Refer to a separate table in UpToDate that defines the categories.|
|VUS||Variant of uncertain significance (or unknown significance). Refers to a variant for which insufficient information is available to classify as benign or pathogenic.|
|Pathogenic||Associated with disease risk|
|Likely pathogenic||>90% likelihood of disease risk association|
|Variant of uncertain significance (VUS)||Available data do not allow classification into one of the other categories|
|Likely benign||>90% likelihood that variant is not associated with disease risk|
|Benign||Not associated with disease risk|
- Population data (allele frequency; prevalence of variant in affected individuals versus controls)
- Computational data (predicted effect on protein sequence or function)
- Functional data (functional studies show or do not show deleterious effect)
- Segregation data (variant segregates with disorder in families)
Supported by an unrestricted educational grant from AncestryHealth®.
|Any Lynch cancer||59%||80%||71%||75%||31%||71%||-||-|
|Colorectal||34 to 47%||36 to 45%||37 to 47%||33 to 37%||14 to 22%||10 to 26%||19 to 20%||11 to 15%|
|Endometrial||NA||18 to 60%||NA||21 to 60%||NA||16 to 71%||NA||13 to 24%|
|Ovarian||NA||11 to 20%||NA||15 to 24%||NA||0 to 1%||NA||0%|
|Brain tumors (gliomas)||1.7%*||2.5%*||-||-|
* Not reported separately by sex.
- Moller P, Seppala T, Bernstein I, et al. Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance: first report from the prospective Lynch syndrome database. Gut 2017; 66:464.
- Dowty JG, Win AK, Buchanan DD, et al. Cancer risks for MLH1 and MSH2 mutation carriers. Hum Mutat 2013; 34:490.
- Baglietto L, Lindor NM, Dowty JG, et al. Risks of Lynch syndrome cancers for MSH6 mutation carriers. J Natl Cancer Inst 2010; 102:193.
- Senter L, Clendenning M, Sotamaa K, et al. The clinical Phenotype of Lynch syndrome due to germ-line PMS2 mutations. Gastroenterology 2008; 135:419.
- Bonadona V, Bonaiti B, Olschwang S, et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA 2011; 305:2304.
- Ten Broeke SW, Brohet RM, Tops CM, et al. Lynch syndrome caused by germline PMS2 mutations: delineating the cancer risk. J Clin Oncol 2015; 33:319.
- Ten Broeke SW, van der Klift HM, Tops CMJ, et al. Cancer Risks for PMS2-Associated Lynch Syndrome. J Clin Oncol 2018; 36:2961.
- Koornstra JJ, Mourits MJ, Sijmons RH, et al. Management of extracolonic tumours in patients with Lynch syndrome. Lancet Oncol 2009; 10:400.
|Patient population||Intervention(s) that may be appropriate|
|Women (in addition to surveillance and interventions for all individuals above)||
|First- and second-degree relatives||
* Refers to a germline variant; includes variants in MMR genes MLH1, MSH2, MSH6, PMS2, and the EPCAM gene. Pathogenic or likely pathogenic variants in other MMR genes are very rare and management is individualized.
* Ensure that the genetic testing is performed properly, the patient identification is correct, and the interpretation of pathogenicity is accurate based on the most recent data analysis.
¶ Pathogenic and likely pathogenic variants are treated the same for purposes of surveillance and risk reduction interventions; these interventions are independent of family history.
Δ VUSs lack sufficient information from clinical and bench research to be classified as pathogenic or benign. Continue to seek updated interpretation of pathogenicity periodically (eg, annually).
◊ Lynch syndrome cancers include colorectal, endometrial, ovarian, urinary tract, gastric and small bowel, hepatobiliary and pancreatic, brain, and skin. Refer to UpToDate for the age at which interventions are initiated, the frequency at which they are performed (eg, delay of rrBSO until after childbearing), and the evidence to support these interventions.
Contributor DisclosuresDaniel C Chung, MDNothing to discloseLinda H Rodgers, MGC, CGCNothing to discloseBarbara Goff, MDEmployment (Spouse): Lilly [General oncology] - No relevant conflict on topics.Anne Slavotinek, MBBS, PhDGrant/Research/Clinical Trial Support: UCSF [P3EGS project]; National Human Genome Research Institute, National Institutes of Health [Clinical sequencing evidence generating research 2]; Retrophin [CTX, early-onset idiopathic bilateral cataracts (Natural history study testing for cerebrotendinous xanthomatosis)]. Consultant/Advisory Boards: American Board of Medical Genetics and Genomics [Director]; Roche [Alpha globin testing]. Employment: American Journal of Medical Genetics [Deputy Editor]. Other Financial Interest: Oxford University Press [Royalties from book].Jennifer S Tirnauer, MDNothing to discloseShilpa Grover, MD, MPH, AGAFNothing to discloseAlana Chakrabarti, MDNothing to discloseDiane MF Savarese, MDNothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.