Clinical characteristics.

Lynch syndrome is characterized by an increased risk for colorectal cancer (CRC) and cancers of the endometrium, stomach, ovary, small bowel, hepatobiliary tract, urinary tract, brain, and skin. In individuals with Lynch syndrome the following lifetime risks for cancer are seen:

• CRC: 52%-82% (mean age at diagnosis 44-61 years)
• Endometrial cancer in females: 25%-60% (mean age at diagnosis 48-62 years)
• Gastric cancer: 6%-13% (mean age at diagnosis 56 years)
• Ovarian cancer: 4%-12% (mean age at diagnosis 42.5 years; ~30% are diagnosed < age 40 years).

The risk for other Lynch syndrome-related cancers is lower, though substantially increased over general population rates.

Diagnosis/testing.

The diagnosis of Lynch syndrome is established in a proband by identification of a germline heterozygous pathogenic variant in MLH1, MSH2, MSH6, or PMS2 or an EPCAM deletion on molecular genetic testing.

Management.

Treatment of manifestations: For colon cancer, full colectomy with ileorectal anastomosis is recommended. Other tumors are managed as in the general population.

Prevention of primary manifestations: Prophylactic hysterectomy and bilateral salpingo-oophorectomy can be considered after childbearing is completed. Prophylactic colectomy prior to the development of colon cancer is generally not recommended for individuals known to have Lynch syndrome because screening colonoscopy with polypectomy is an effective preventive measure.

Surveillance: Colonoscopy with removal of precancerous polyps every one to two years beginning between age 20 and 25 years or two to five years before the earliest age of diagnosis in the family, whichever is earlier. The efficacy of surveillance for cancer of the endometrium, ovary, stomach, duodenum, distal small bowel, urinary tract, and central nervous system is unknown.

Agents/circumstances to avoid: Cigarette smoking.

Evaluation of relatives at risk: When a diagnosis of Lynch syndrome has been confirmed in a proband, molecular genetic testing for the Lynch syndrome-related pathogenic variant should be offered to first-degree relatives to identify those who would benefit from early surveillance and intervention. Although molecular genetic testing for Lynch syndrome is generally not recommended for at-risk individuals younger than age 18 years, a history of early cancers in the family may warrant predictive testing prior to age 18.

Genetic counseling.

Lynch syndrome is inherited in an autosomal dominant manner. The majority of individuals diagnosed with Lynch syndrome have inherited the condition from a parent. However, because of incomplete penetrance, variable age of cancer development, cancer risk reduction as a result of screening or prophylactic surgery, or early death, not all individuals with a pathogenic variant in one of the genes associated with Lynch syndrome have a parent who had cancer. Each child of an individual with Lynch syndrome has a 50% chance of inheriting the pathogenic variant. Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant in the family is known.

Suggestive Findings

A diagnosis of Lynch syndrome should be suspected in a proband with:

• A diagnosis of colorectal cancer (CRC) or endometrial cancer and one or more of the following*:
  • Colorectal or endometrial cancer diagnosed before age 50 years
  • Synchronous or metachronous Lynch syndrome-related cancers (e.g., colorectal, endometrial, stomach, small intestinal, hepatobiliary, renal pelvic, ureteral)
  • Colorectal tumor tissue with MSI-high histology (e.g., poor differentiation, tumor-infiltrating lymphocytes, Crohn's-like lymphocytic reaction, mucinous/signet-ring differentiation, medullary growth pattern)
  • Microsatellite instability (MSI) testing showing that tumor tissue (e.g., colon, endometrial) is MSI-high (For information on MSI testing including advantages and disadvantages, click here.)
  • Tumor tissue (e.g., colon, endometrial) immunohistochemistry (IHC) demonstrates loss of expression of one or more of the mismatch repair (MMR) gene products: MSH2, MLH1, MSH6, and PMS2. (For information on advantages and disadvantages of IHC testing, click here.)
  • At least one first-degree relative with any Lynch syndrome-related cancer diagnosed before age 50 years
  • At least two first-degree relatives with any Lynch syndrome-related cancers regardless of age of cancer diagnosis
• A family member with colorectal or endometrial cancer who meets one of the above criteria
  Note: Molecular genetic testing ideally begins with a person who has had a Lynch syndrome-related cancer. However, in some families there may be no affected individual who is alive or willing to be tested.
• A family member with a confirmed diagnosis of Lynch syndrome
• A greater-than-5% probability of having a pathogenic variant in one of the genes listed in Table 1 based on risk assessment models
  Note: Several risk assessment models including PREMM_1,2,6 [Kastrinos et al 2011] and MMRPro [Chen et al 2006] predict the likelihood of identifying a germline pathogenic variant in one of the genes listed in Table 1. Both models have good predictive value in a clinical and population-based setting when using a 5% threshold for testing [Win et al 2013a, Kastrinos et al 2015].

*Adapted from revised Bethesda Guidelines and National Comprehensive Cancer Network (NCCN) Guidelines; click here (no-fee registration and log-in required).

Population screening strategies for Lynch syndrome. Lynch syndrome screening guidelines for individuals with CRC have been developed by the NCCN; click here (no-fee registration and log-in required). The Lynch Syndrome Screening Network was established to help develop best-practice approaches for screening individuals with Lynch syndrome-related cancers and to collect long-term data on the outcomes of these programs [Mange et al 2015].

Screening approaches include:

• Screen all CRC with MSI or IHC testing. This was shown to be a cost-effective approach for identifying individuals who should be offered germline molecular genetic testing for Lynch syndrome [EGAPP 2009, Ladabaum et al 2011]. (For information on advantages and disadvantages of IHC testing, click here. For information on MSI testing including advantages and disadvantages, click here.)
• Screen all CRC and endometrial cancers with MSI or IHC testing [EGAPP 2009, Mange et al 2015].
• Use age of onset and pathologic features to predict which individuals are more likely to have a germline MMR pathogenic variant [Rabban et al 2014].

Targeted molecular genetic testing on tumor tissue should be considered in individuals with MLH1/PMS2 loss of expression on IHC. Targeted testing includes the following:

• Targeted analysis of BRAF pathogenic variant p.Val600Glu
  Note: (1) BRAF p.Val600Glu is not present in Lynch syndrome-associated colorectal tumors (see Differential Diagnosis, Sporadic colorectal cancer). (2) BRAF pathogenic variants are not common in sporadic endometrial cancers; thus, BRAF testing is not helpful in distinguishing endometrial cancers that are sporadic from those that are Lynch syndrome related.
• MLH1 promoter methylation analysis on tumor tissue
  Note: Lynch syndrome-related cancers do not have hypermethylation of the MLH1 promoter (see Differential Diagnosis, Sporadic colorectal cancer).

Establishing the Diagnosis

The diagnosis of Lynch syndrome is established in a proband by identification of a heterozygous germline pathogenic variant in one of the genes listed in Table 1.

Molecular genetic testing approaches can include a multigene panel, serial single-gene testing, and more comprehensive genomic testing.

Clinical Description

Individuals with Lynch syndrome are at increased risk for colorectal cancer (CRC) and other cancers including cancers of the endometrium, ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin (Table 3).

Colorectal cancer. The risk of colorectal cancer (CRC) associated with MLH1 and MHS2 pathogenic variants is significantly higher than the risk associated with MSH6 or PMS2 pathogenic variants. The mean ages at onset for CRC in individuals with MSH6 and PMS2 pathogenic variants are also older than for onset for CRC associated with MLH1 and MSH2 pathogenic variants, 54-63 years and 47-66 years respectively. However, up to 8% of CRCs in PMS2 heterozygotes occur before age 30. Therefore, individuals with MLH6 or PMS2 pathogenic variants should follow the same CRC screening recommendations as MLH1 and MSH2 heterozygotes. A 2009 study of a Finnish cohort with high compliance with screening found no increase in mortality for individuals with Lynch syndrome compared to relatives without the Lynch syndrome-related pathogenic variant, indicating that annual colonoscopy is effective for the prevention and detection of CRC [Järvinen et al 2009].

Data on cancer risks for those with an EPCAM deletion is still limited, but Kempers et al [2011] reported on findings from 194 individuals with an EPCAM deletion. From this cohort they estimated a 75% (95% CI 65-86) cumulative incidence of CRC by age 70 years. The risk for CRC did not differ between those who had only a 3' deletion of EPCAM and those individuals with a deletion that encompassed EPCAM and MSH2. However, only those with an EPCAM deletion that includes MSH2 are at an increased risk for extracolonic cancers [Kempers et al 2011, Tutlewska et al 2013].

Tumors that are MSI-H, either due to sporadic causes or an underlying germline MMR pathogenic variant, tend to have a better prognosis than MSS tumors [Kawakami et al 2015].

Endometrial cancer. The risk for women with EPCAM deletions that encompass MSH2 is similar to that for individuals with MSH2 pathogenic variants.

Among females with Lynch syndrome who develop both CRC and endometrial cancer, approximately 50% present first with endometrial cancer [Lu et al 2005]. The risk for subsequent endometrial cancer to females with Lynch syndrome presenting first with CRC has been estimated at 26% within ten years of the initial CRC diagnosis [Obermair et al 2010].

Overall, a survival advantage similar to that in Lynch syndrome-related CRC has been reported in Lynch syndrome-related endometrial cancers [Maxwell et al 2001].

Gastric cancer. Intestinal-type adenocarcinoma, the most commonly reported pathology of Lynch syndrome-related gastric cancers [Aarnio et al 1997], differs histologically from the diffuse gastric cancer that is most commonly seen in hereditary diffuse gastric cancer caused by pathogenic variants in CDH1 [Guilford et al 1999]. However, Capelle et al [2010] reported that up to 20% of Lynch syndrome-related gastric cancers may be the diffuse type. The risk for gastric cancer is higher in individuals with Lynch syndrome who reside in countries with a high incidence of H pylori infection [Park et al 2000].

Ovarian cancer risk to females with a germline MLH1 or MSH2 pathogenic variant has been found to be 4%-20%. The mean age of diagnosis of Lynch syndrome-associated ovarian cancer has been reported at between age 43 and 45 years, although diagnosis at very young ages has been reported. Approximately 30% of Lynch syndrome-associated ovarian cancers are diagnosed before age 35 years [Watson et al 2008].

The distribution of pathology types is similar to that seen in sporadic ovarian cancers. Borderline ovarian tumors do not appear to be associated with Lynch syndrome [Watson et al 2001].

Small bowel cancer. The duodenum and jejunum are the most common sites for small bowel cancers, with approximately 50% in reach of upper endoscopy [Schulmann et al 2005]. The majority of small bowel cancers are adenocarcinomas [Rodriguez-Bigas et al 1998, Schulmann et al 2005].

Urinary tract cancers. The urinary tract cancers most commonly associated with Lynch syndrome are transitional carcinomas of the ureter and renal pelvis.

Bladder cancer risk is also likely increased in individuals with Lynch syndrome. A study of Dutch individuals with Lynch syndrome demonstrated a relative risk for bladder cancer of 4.4 for males and 2.2 for females; the majority of tumor tissue available for testing was MSI-H and/or had loss of protein expression by IHC [van der Post et al 2010].

Individuals with Lynch syndrome and a prior diagnosis of CRC were also at increased risk for subsequent bladder cancer (7.22, 95% CI=4.08-10.99) and other urinary tract cancers (kidney, renal pelvis, and ureter) (12.54, 95% CI 7.97-17.94) [Win et al 2013b].

Risk estimates for urinary tract cancers vary significantly based on gender and the gene involved.

Brain tumors. The most common type of central nervous system tumor is glioblastoma [Hamilton et al 1995, Wimmer & Etzler 2008]. The brain tumors associated with pathogenic variants in an MMR gene are typically MSI-H [Hamilton et al 1995, Suzui et al 1998].

Sebaceous neoplasms described in individuals with Lynch syndrome include: sebaceous adenomas, sebaceous epitheliomas, sebaceous carcinomas, and keratoacanthomas. Sebaceous neoplasms associated with Lynch syndrome are typically MSI-H [Entius et al 2000, Machin et al 2002]. Data on the frequency of sebaceous neoplasms in individuals with Lynch syndrome are limited. Studies have found that between 1% and 9% of individuals with a germline pathogenic variant in an MMR gene have a sebaceous neoplasm [Ponti et al 2006, South et al 2008].

Phenotype Correlations by Gene

Cancer risks vary among the genes associated with Lynch syndrome.

MSH2. Heterozygosity for an MSH2 pathogenic variant is associated with the greatest risk for extracolonic cancers.

MSH2 pathogenic variants have been reported more commonly than a pathogenic variant in the other three MMR genes in individuals with the Muir-Torre variant of Lynch syndrome [South et al 2008].

MSH6. Heterozygosity for a pathogenic variant in MSH6 is associated with MSI-low tumors. The colorectal cancers in families with an MSH6 pathogenic variant may be later in onset and more distally located than the cancers in families with Lynch syndrome resulting from a pathogenic variant in one of the other MMR genes; endometrial cancer is commonly observed in females with an MSH6 pathogenic variant [Wu et al 1999, Berends et al 2002]. Slightly lower risks for colorectal cancer and higher risks for endometrial cancer have been reported in families with an MSH6 pathogenic variant than in families with an MLH1 or MSH2 pathogenic variant [Berends et al 2002, Baglietto et al 2010].

PMS2. Heterozygosity for a PMS2 pathogenic variant is associated with the lowest risk (25%-32% risk) for any Lynch syndrome-related cancer [Senter et al 2008]. However, while the overall risk of CRC is lower, age of onset may still be early. A review of 234 PMS2 pathogenic variant carriers found that 8% were diagnosed before age 30 [Goodenberger et al 2016].

EPCAM. Deletions of EPCAM that result in epigenetic silencing of MSH2 are associated with a significantly increased risk for colorectal cancer. Kempers et al [2011] reported a low risk for endometrial cancer in those with deletions of EPCAM compared to pathogenic variants in an MMR gene.

Genotype-Phenotype Correlations

EPCAM. The risk for extracolonic cancers is dependent on the size of the deletion. 3' EPCAM deletions have been shown to confer a lower risk for extracolonic cancers, whereas deletions that extend into MSH2 confer extracolonic cancer risks similar to intragenic MSH2 pathogenic variants [Tutlewska et al 2013].

Penetrance

Penetrance of CRCs and extracolonic cancers associated with pathogenic variants in an MMR gene or EPCAM is less than 100% (see Table 3). Therefore, some individuals with a cancer-predisposing pathogenic variant in an MMR gene or EPCAM may never develop cancer.

Nomenclature

Lynch syndrome has also been called hereditary non-polyposis colorectal cancer (HNPCC). Clinicians and researchers working in the area of hereditary colorectal cancer have suggested returning to the use of the original name, Lynch syndrome, to include individuals and families with confirmed pathogenic variants in an MMR gene or EPCAM.

Prevalence

Lynch syndrome accounts for approximately 1%-3% of CRCs and 0.8%-1.4% of endometrial cancers [Kowalski et al 1997, Chadwick et al 2001, Cunningham et al 2001].

The population prevalence of Lynch syndrome has been estimated at 1:440 [Chen et al 2006].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Lynch syndrome, the evaluations summarized in Surveillance are recommended, as well as consultation with a clinical geneticist and/or genetic counselor.

Treatment of Manifestations

Management of colon cancer in a person with Lynch syndrome. If colon cancer is detected, full colectomy with ileorectal anastomosis is recommended rather than a segmental/partial colonic resection because of the high risk for metachronous cancers. A meta-analysis of six studies including a total of 871 individuals found that based on an average of 91 months' follow up, the rate of metachronous cancers was 23% among those individuals who had a segmental colectomy, compared to 6% among individuals who had a colectomy (colectomy defined as subtotal or colectomy with ileosigmoid anastomosis) [Anele et al 2017].

Population-based approaches for screening newly diagnosed individuals with CRC for Lynch syndrome generally rely on analysis of tumor tissue from the surgical resection specimen, but this will not provide information about the diagnosis of Lynch syndrome in time to make decisions about segmental/partial colectomy versus colectomy. For individuals presenting with CRC before age 50 and/or who have a strong family history, proceeding directly to genetic testing could be considered in order to have information about possible hereditary diagnoses in time for surgical planning.

The other tumors seen in Lynch syndrome are managed as in the general population.

Prevention of Primary Manifestations

Prophylactic hysterectomy and bilateral salpingo-oophorectomy can be considered after childbearing is completed.

Because screening colonoscopy with polypectomy is an effective preventive measure for colorectal cancer, prophylactic colectomy (removal of the colon prior to the development of cancer) is generally not recommended for individuals with Lynch syndrome.

Aspirin therapy has been shown to decrease the risk for CRC in individuals with Lynch syndrome (see Therapies Under Investigation).

Surveillance

Colorectal cancer (CRC). Colonoscopy with removal of precancerous polyps should be performed every one to two years beginning between age 20 and 25 years or two to five years before the earliest diagnosis in the family, whichever is earlier, for all individuals with Lynch syndrome. Regular colonoscopy with removal of precancerous polyps reduces the incidence of CRC in individuals with Lynch syndrome.

Colonoscopy is recommended rather than flexible sigmoidoscopy because of the predominance of proximal colon cancers in Lynch syndrome.

Endometrial cancer. Endometrial cancer surveillance is less well established than that for colon cancer.

Educate females about the symptoms of endometrial cancers (e.g., abnormal uterine bleeding, postmenopausal bleeding), because many endometrial cancers can be diagnosed at early stages on the basis of symptoms.

Endometrial biopsy every one to two years can be considered, but to date data do not support that such additional testing improves early detection or outcomes [NCCN 2016].

Studies on the effectiveness of transvaginal ultrasound examination and endometrial biopsy have had conflicting results:

• In a study of the use of transvaginal ultrasound examination to screen for endometrial cancer, no cancers were detected; however, two cancers were detected on the basis of symptoms manifest during the course of the study [Dove-Edwin et al 2002].
• A report from a Finnish cohort found that endometrial sampling and transvaginal ultrasound every two to three years resulted in the diagnosis of early-stage cancers. However, because endometrial cancer often presents with symptoms at an early stage, it was not clear that the screening improved detection [Järvinen et al 2009].

Ovarian cancer. No specific ovarian cancer screening trials have been conducted in females with Lynch syndrome.

Educate women about the symptoms that may be associated with ovarian cancer (e.g., pelvic or abdominal pain, bloating, increased abdominal girth, difficulty eating, early satiety, urinary frequency or urgency).

Screening for ovarian cancer using serum CA-125 and transvaginal ultrasound examination has not been effective in other high-risk populations such as females with a BRCA1 or BRCA2 pathogenic variant [Evans et al 2009], but may be recommended at the clinician's discretion.

Gastric and duodenal cancers. Over time, screening recommendations for gastric and duodenal cancers have varied. Studies have not supported that screening improves early detection or outcomes of these cancers, but because the stomach and duodenum are the most common extracolonic non-gynecologic cancer in Lynch syndrome, periodic upper endoscopy exams have been included in guidelines. Upper endoscopy can be considered, particularly for individuals with a family history of gastric cancer and those of Asian ancestry, every three to five years beginning between age 30 and 35 years [NCCN 2016]. Note: Biopsies should be evaluated for H pylori infections so that appropriate treatment can be given as needed [NCCN 2016].

Data regarding the effectiveness of upper endoscopy examination for the early detection of gastric cancer in Lynch syndrome are limited.

• One study suggested no benefit from this screening for gastric cancer because of the lack of identifiable precursor lesions [Renkonen-Sinisalo et al 2002].
• A study looking at gastric cancer risk in a Dutch study suggested that the level of risk is sufficient to warrant screening; however, since 87% of the cancers occurred after age 45 years, it may be most cost effective to initiate screening at age 45 years [Capelle et al 2010].
• Schulmann et al [2005] found that approximately 50% of the small bowel cancers in a cohort with Lynch syndrome were located in the duodenum, suggesting that upper endoscopy may be useful for screening. However, no trials to determine the efficacy of upper endoscopy for screening for duodenal cancers have been conducted.

Distal small bowel. Data are limited regarding screening for cancer in the distal small bowel. Capsule endoscopy and small bowel enterography are available for evaluating the small bowel, but at this time, there is no recommendation for routine use of these approaches for small bowel screening, although they may be helpful for evaluating symptomatic individuals.

Urinary tract. NCCN recommends consideration of annual urine analysis beginning between age 30 and 35 years [NCCN 2016].

Central nervous system. Consider an annual physical exam that includes a neurologic evaluation beginning at age 25 to 30 years. At this time, there is no recommendation for routine imaging to screen for brain tumors.

Other cancers. At this time, no specific screening recommendations for other Lynch syndrome-associated cancers exist. Individuals should be encouraged to follow other general population screening guidelines and to seek prompt medical attention for changes in health or persistent symptoms. As noted previously, individuals with Lynch syndrome may be at increased risk for other cancers such as breast and prostate. However, it is not clear that these risks warrant screening above and beyond what is currently recommended for general population screening for these cancers. If there is a family history of early onset of other cancer types, cancer screening recommendations should be adjusted to begin screening at an earlier age.

Agents/Circumstances to Avoid

Cigarette smoking increases the risk for CRC in Lynch syndrome [Pande et al 2010].

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of all first-degree relatives (parents, sibs, and children) of an affected individual by molecular genetic testing for the Lynch syndrome-related pathogenic variant in the family in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures.

Early recognition of cancers associated with Lynch syndrome may allow for timely intervention and improved final outcome.

• Sibs should be considered at risk even if the parents have not had cancer because most Lynch syndrome results from an inherited (not de novo) pathogenic variant.
• If clinical history and family history cannot identify the parent from whom the proband inherited the Lynch syndrome-related pathogenic variant, molecular genetic testing should be offered to both parents to determine which has the pathogenic variant.

In general, molecular genetic testing for Lynch syndrome is not recommended for at-risk individuals younger than age 18 years. However, predictive testing should be considered if there is a history of early-onset cancer in the family. For unaffected individuals with a Lynch syndrome-related pathogenic variant, screening should begin between age 20 and 25 years, or two to five years earlier than the earliest diagnosis in the family [NCCN 2016]. Therefore, a history of early cancers in the family may also warrant testing prior to age 18.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Ideally cancer screening exams would be planned around a pregnancy. An affected female would be encouraged to be current on her cancer screening before attempting to become pregnant. If an affected female is diagnosed with cancer during pregnancy, she should be counseled about cancer treatment options and their potential implications for the fetus.

Therapies Under Investigation

Mode of Inheritance

Lynch syndrome is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• The majority of individuals diagnosed with Lynch syndrome inherited a pathogenic variant from a parent who may or may not have had cancer.
• A parent heterozygous for a Lynch syndrome-related pathogenic variant may not have had cancer because of incomplete penetrance, variable age of cancer development, cancer risk reduction resulting from screening or prophylactic surgery, or early death.
• If clinical and family history cannot identify the parent from whom the proband inherited the pathogenic variant, molecular genetic testing should be offered to both parents to determine which one has the pathogenic variant identified in the proband.
• In the rare event that the pathogenic variant found in the proband is not detected in leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband. The precise de novo pathogenic variant rate for Lynch syndrome is unknown but estimated to be extremely low [Bisgaard & Bernstein 2003].

Sibs of a proband

• Sibs of a proband are at a 50% risk of inheriting the pathogenic variant.
• Molecular genetic testing for the familial Lynch syndrome-related variant should be offered to all sibs.
• Even if the parents have not had cancer, sibs should still be considered at risk and offered molecular genetic testing because most Lynch syndrome-related pathogenic variants are inherited, not de novo.

Offspring of a proband. Each child of an individual with Lynch syndrome has a 50% chance of inheriting the Lynch syndrome-related pathogenic variant.

Other family members. The risk to other family members depends on their relationship to the proband. Family history or molecular genetic testing can help determine whether maternal or paternal relatives are at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Specific risk issues. Several factors can hinder the diagnosis of Lynch syndrome based on family history. Screening and removal of precancerous polyps and prophylactic surgery may prevent colon or endometrial cancer in some at-risk relatives; some who died young from other causes may never have developed cancer.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with Lynch syndrome has the pathogenic variant or clinical evidence of Lynch syndrome, it is possible that the proband has a de novo pathogenic variant. However, a de novo pathogenic variant is thought to be rare, and non-medical explanations, including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption, could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Genetic cancer risk assessment and counseling. For a comprehensive description of the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without molecular genetic testing, see Cancer Genetics Risk Assessment and Counseling – for health professionals (part of PDQ^®, National Cancer Institute).

Predictive testing (i.e., testing of asymptomatic at-risk individuals)

• Predictive testing for at-risk relatives is possible once the Lynch syndrome-related pathogenic variant has been identified in an affected family member.
• Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.

Predictive testing in minors (i.e., testing of asymptomatic at-risk individuals younger than age 18 years)

• In general, genetic testing for Lynch syndrome is not recommended for at-risk individuals younger than age 18 years. However, predictive testing should be considered if there is a history of early-onset cancer in the family. In unaffected individuals with a Lynch syndrome-related pathogenic variant, screening is recommended beginnning at age 20 to 25 years, or two to five years prior to the earliest diagnosis in the family [NCCN 2016]. Therefore, a history of early cancers in the family may also warrant testing prior to age 18.
• For more information, see the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the Lynch syndrome-related pathogenic variant has been identified in an affected family member, prenatal testing and preimplantation genetic diagnosis are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Molecular Genetic Pathogenesis

Lynch syndrome is caused by pathogenic variants in genes involved with the mismatch repair (MMR) pathway. This pathway functions to identify and remove single-nucleotide mismatches or insertions and deletion loops. Pathogenic variants in four of the MMR genes can cause Lynch syndrome [Peltomäki 2003]. The functions of the MMR genes can be disrupted by missense variants, truncating variants, splice site variants, large deletions, or genomic rearrangements. In addition, germline deletions within EPCAM, which is not an MMR gene, can disrupt the MMR pathway by inactivating the adjacent MMR gene MSH2, even though MSH2 itself has not been mutated.

Published Guidelines / Consensus Statements

• American College of Medical Genetics technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis). Available online. 2014. Accessed 7-24-18. [PubMed: 24310308]
• American College of Medical Genetics/American Society of Human Genetics. Joint statement on genetic testing for colon cancer (pdf). Available online. 2000. Accessed 7-24-18.
• American Gastroenterological Association. Medical position statement: hereditary colorectal cancer and genetic testing (pdf). Available online. 2001. Accessed 7-24-18.
• American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. Available online. 2010. Accessed 7-24-18.
• American Society of Colon and Rectal Surgeons. Practice parameters for the treatment of patients with dominantly inherited colorectal cancer (FAP and HNPCC). Available online. 2003. Accessed 7-24-18.
• Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available online. 2013. Accessed 7-24-18. [PubMed: 23428972]
• Giardiello FM, Brensinger JD, Petersen GM. American Gastroenterological Association technical review on hereditary colorectal cancer and genetic testing. Gastroenterology. 2001;121:198–213. [PubMed: 11438509]
• Lu KH, Wood ME, Daniels M, Burke C, Ford J, Kauff ND, Kohlmann W, Lindor NM, Mulvey TM, Robinson L, Rubinstein WS, Stoffel EM, Snyder C, Syngal S, Merrill JK, Wollins DS, Hughes KS, et al. American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers. J Clin Oncol. 2014;32:833–40. [PMC free article: PMC3940540] [PubMed: 24493721]
• National Comprehensive Cancer Network. Guidelines for colorectal cancer screening. 2016.
• National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available online. 2017. Accessed 7-24-18.
• Weissman SM, Burt R, Church J, Erdman S, Hampel H, Holter S, Jasperson K, Kalady MF, Haidle JL, Lynch HT, Palaniappan S, Wise PE, Senter L. Identification of individuals at risk for Lynch syndrome using targeted evaluations and genetic testing: National Society of Genetic Counselors and the Collaborative Group of the Americas on Inherited Colorectal Cancer joint practice guideline. J Genet Couns. 2012;21:484–93. [PubMed: 22167527]

Literature Cited

• Aarnio M, Salovaara R, Aaltonen LA, Mecklin JP, Jarvinen HJ. Features of gastric cancer in hereditary non-polyposis colorectal cancer syndrome. Int J Cancer. 1997;74:551–5. [PubMed: 9355980]
• Abdel-Rahman WM, Ollikainen M, Kariola R, Jarvinen HJ, Mecklin JP, Nystrom-Lahti M, Knuutila S, Peltomaki P. Comprehensive characterization of HNPCC-related colorectal cancers reveals striking molecular features in families with no germline mismatch repair gene mutations. Oncogene. 2005;24:1542–51. [PubMed: 15674332]
• Anele CC, Adegbola SO, Askari A, Rajendran A, Clark SK, Latchford A, Faiz OD. Risk of metachronous colorectal cancer following colectomy in Lynch syndrome: a systematic review and meta-analysis. Colorectal Dis. 2017;19:528–36. [PubMed: 28407411]
• Baglietto L, Lindor NM, Dowty DM, Wagner A, Gomez Garcia EB, Vriends AH., Dutch Lynch Syndrome Study Group. Cartwright NR, Barnetson RA, Farrington SM, Tenesa A, Hampel H, Buchanan D, Arnold S, Young J, Walsh MD, Jass J, Macrae F, Antill Y, Winship IM, Giles GG, Goldblatt J, Parry S, Suthers G, Leggett B, Butz M, Aronson M, Poynter JN, Baron JA, Le Marchand L, Haile R, Gallinger S, Hopper JL, Potter J, de la Chapelle A, Vasen HF, Dunlop MG, Thibodeau SN, Jenkins MA. Risks of Lynch syndrome cancers for MSH6 mutation carriers. J Natl Cancer Inst. 2010;102:193–201. [PMC free article: PMC2815724] [PubMed: 20028993]
• Bakry D, Aronson M, Durno C, Rimawi H, Farah R, Alharbi QK, Alharbi M, Shamvil A, Ben-Shachar S, Mistry M, Constantini S, Dvir R, Qaddoumi I, Gallinger S, Lerner-Ellis J, Pollett A, Stephens D, Kelies S, Chao E, Malkin D, Bouffet E, Hawkins C, Tabori U. Genetic and clinical determinants of constitutional mismatch repair deficiency syndrome: report from the constitutional mismatch repair deficiency consortium. Eur J Cancer. 2014;50:987–96. [PubMed: 24440087]
• Barrow E, Robinson L, Alduaij W, Shenton A, Clancy T, Lalloo F, Hill J, Evans DG. Cumulative lifetime incidence of extracolonic cancers in Lynch syndrome: a report of 121 families with proven mutations. Clin Genet. 2009;75:141–9. [PubMed: 19215248]
• Bellido F, Pineda M, Aiza G, Valdés-Mas R, Navarro M, Puente DA, Pons T, González S, Iglesias S, Darder E, Piñol V, Soto JL, Valencia A, Blanco I, Urioste M, Brunet J, Lázaro C, Capellá G, Puente XS, Valle L. POLE and POLD1 mutations in 529 kindreds with familial colorectal cancer and/or polyposis: a review of reported cases and recommendations for genetic testing and surveillance. Genet Med. 2016;18:325–32. [PMC free article: PMC4823640] [PubMed: 26133394]
• Bellizzi AM, Frankel WL. Colorectal cancer due to deficiency in DNA mismatch repair function: a review. Adv Anat Pathol. 2009;16:405–17. [PubMed: 19851131]
• Berends MJ, Wu Y, Sijmons RH, Mensink RG, van der Sluis T, Hordijk-Hos JM, de Vries EG, Hollema H, Karrenbeld A, Buys CH, van der Zee AG, Hofstra RM, Kleibeuker JH. Molecular and clinical characteristics of MSH6 variants: an analysis of 25 index carriers of a germline variant. Am J Hum Genet. 2002;70:26–37. [PMC free article: PMC384896] [PubMed: 11709755]
• Billingsley CC, Cohn DE, Mutch DG, Stephens JA, Suarez AA, Goodfellow PJ. Polymerase e (POLE) mutations in endometrial cancer: clinical outcomes and implcations for Lynch syndrome testing. Cancer. 2015;121:386–94. [PMC free article: PMC4304930] [PubMed: 25224212]
• Bisgaard ML, Bernstein I. HNPCC mutation rate (published abstract). Familial Cancer. 2003;2:56.
• Bisschops R, Tejpar S, Willekens H, Hertogh GD, Van Cutsem E. Virtual chromoenscopy (I-SCAN) detects more polyps in patients with Lynch syndrome: a randomized controlled crossover trial. Endoscopy. 2017;49:342–50. [PubMed: 28107763]
• Bonadona V, Bonaïti B, Olschwang S, Grandjouan S, Huiart L, Longy M, Guimbaud R, Buecher B, Bignon YJ, Caron O, Colas C, Noguès C, Lejeune-Dumoulin S, Olivier-Faivre L, Polycarpe-Osaer F, Nguyen TD, Desseigne F, Saurin JC, Berthet P, Leroux D, Duffour J, Manouvrier S, Frébourg T, Sobol H, Lasset C, Bonaïti-Pellié C., French Cancer Genetics Network. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA. 2011;305:2304–10. [PubMed: 21642682]
• Bouzourene H, Hutter P, Losi L, Martin P, Benhattar J. Selection of patients with germline MLH1 mutated Lynch syndrome by determination of MLH1 methylation and BRAF mutation. Fam Cancer. 2010;9:167–72. [PubMed: 19949877]
• Burn J, Bishop DT, Mecklin JP, Macrae F, Möslein G, Olschwang S, Bisgaard ML, Ramesar R, Eccles D, Maher ER, Bertario L, Jarvinen HJ, Lindblom A, Evans DG, Lubinski J, Morrison PJ, Ho JW, Vasen HF, Side L, Thomas HJ, Scott RJ, Dunlop M, Barker G, Elliott F, Jass JR, Fodde R, Lynch HT, Mathers JC. CAPP2 Investigators. Effect of aspirin or resistant starch on colorectal neoplasia in the Lynch syndrome. N Engl J Med. 2008;359:2567–78. [PubMed: 19073976]
• Burn J, Gerdes AM, Macrae F, Mecklin JP, Moeslein G, Olschwang S, Eccles D, Evans DG, Maher ER, Bertario L, Bisgaard ML, Dunlop MG, Ho JW, Hodgson SV, Lindblom A, Lubinski J, Morrison PJ, Murday V, Ramesar R, Side L, Scott RJ, Thomas HJ, Vasen HF, Barker G, Crawford G, Elliott F, Movahedi M, Pylvanainen K, Wijnen JT, Fodde R, Lynch HT, Mathers JC, Bishop DT. CAPP2 Investigators. Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet. 2011;378:2081–7. [PMC free article: PMC3243929] [PubMed: 22036019]
• Capelle LG, Van Grieken NC, Lingsma HF, Steyerberg EW, Klokman WJ, Bruno MJ, Vasen HF, Kuipers EJ. Risk and epidemiological time trends of gastric cancer in Lynch syndrome carriers in the Netherlands. Gastroenterology. 2010;138:487–92. [PubMed: 19900449]
• Chadwick RB, Pyatt RE, Niemann TH, Richards SK, Johnson CK, Stevens MW, Meek JE, Hampel H, Prior TW, de la Chapelle A. Hereditary and somatic DNA mismatch repair gene mutations in sporadic endometrial carcinoma. J Med Genet. 2001;38:461–6. [PMC free article: PMC1757178] [PubMed: 11474654]
• Chen S, Wang W, Lee S, Nafa K, Lee J, Romans K, Watson P, Gruber SB, Euhus D, Kinzler KW, Jass J, Gallinger S, Lindor NM, Casey G, Ellis N, Giardiello FM, Offit K, Parmigiani G. Colon Cancer Family Registry. Prediction of germline mutations and cancer risk in the Lynch syndrome. JAMA. 2006;296:1479–87. [PMC free article: PMC2538673] [PubMed: 17003396]
• Cunningham JM, Kim CY, Christensen ER, Tester DJ, Parc Y, Burgart LJ, Halling KC, McDonnell SK, Schaid DJ, Walsh Vockley C, Kubly V, Nelson H, Michels VV, Thibodeau SN. The frequency of hereditary defective mismatch repair in a prospective series of unselected colorectal carcinomas. Am J Hum Genet. 2001;69:780–90. [PMC free article: PMC1226064] [PubMed: 11524701]
• Dashti SG, Chau R, Ouakrim DA, Buchanan DD, Clendenning M, Young JP, Winship IM, Arnold J, Ahnen DJ, Haile RW, Casey G, Gallinger S, Thibodeau SN, Lindor NM, Le Marchand L, Newcomb PA, Potter JD, Baron JA, Hopper JL, Jenkins MA, Win AK. Female hormonal factors and the risk of endometrial cancer in Lynch syndrome. JAMA. 2015;314:61–71. [PMC free article: PMC4688894] [PubMed: 26151267]
• den Bakker MA, Seynaeve C, Kliffen M, Dinjens WN. Microsatellite instability in a pleomorphic rhabdomyosarcoma in a patient with hereditary non-polyposis colorectal cancer. Histopathology. 2003;43:297–9. [PubMed: 12940783]
• Dove-Edwin I, Boks D, Goff S, Kenter GG, Carpenter R, Vasen HF, Thomas HJ. The outcome of endometrial carcinoma surveillance by ultrasound scan in women at risk of hereditary nonpolyposis colorectal carcinoma and familial colorectal carcinoma. Cancer. 2002;94:1708–12. [PubMed: 11920532]
• Durno CA, Holter S, Sherman PM, Gallinger S. The gastrointestinal phenotype of germline biallelic mismatch repair gene mutations. Am J Gastroenterol. 2010;105:2449–56. [PubMed: 20531397]
• EGAPP. Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group. Recommendations from the EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives. Genet Med. 2009;11:35–41. [PMC free article: PMC2743612] [PubMed: 19125126]
• Entius MM, Keller JJ, Drillenburg P, Kuypers KC, Giardiello FM, Offerhaus GJ. Microsatellite instability and expression of hMLH-1 and hMSH-2 in sebaceous gland carcinomas as markers for Muir-Torre syndrome. Clin Cancer Res. 2000;6:1784–9. [PubMed: 10815898]
• Evans DG, Gaarenstroom KN, Stirling D, Shenton A, Maehle L, Dørum A, Steel M, Lalloo F, Apold J, Porteous ME, Vasen HF, van Asperen CJ, Moller P. Screening for familial ovarian cancer: poor survival of BRCA1/2 related cancers. J Med Genet. 2009;46:593–7. [PubMed: 18413372]
• Fishel R, Lescoe MK, Rao MR, Copeland NG, Jenkins NA, Garber J, Kane M, Kolodner R. The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell. 1993;75:1027–38. [PubMed: 8252616]
• Gargiulo S, Torrini M, Ollila S, Nasti S, Pastorino L, Cusano R, Bonelli L, Battistuzzi L, Mastracci L, Bruno W, Savarino V, Sciallero S, Borgonovo G, Nyström M, Bianchi-Scarrà G, Mareni C, Ghiorzo P. Germline MLH1 and MSH2 mutations in Italian pancreatic cancer patients with suspected Lynch syndrome. Fam Cancer. 2009;8:547–53. [PubMed: 19728162]
• Giardiello FM, Allen JI, Axilbund JE, Boland CR, Burke CA, Burt RW, Church JM, Dominitz JA, Johnson DA, Kaltenbach T, Levin TR, Lieberman DA, Robertson DJ, Syngal S, Rex DK. 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;109:1159–79. [PubMed: 25070057]
• Goel A, Nguyen TP, Leung HC, Nagasaka T, Rhees J, Hotchkiss E, Arnold M, Banerji P, Koi M, Kwok CT, Packham D, Lipton L, Boland CR, Ward RL, Hitchins MP. De novo constitutional MLH1 epimutations confer early-onset colorectal cancer in two new sporadic Lynch syndrome cases, with derivation of the epimutation on the paternal allele in one. Int J Cancer. 2011;128:869–78. [PMC free article: PMC3794437] [PubMed: 20473912]
• Goodenberger ML, Thomas BC, Riegert-Johnson D, Boland CR, Plon SE, Clendenning M, Win AK, Senter L, Lipkin SM, Stadler ZK, Macrae FA, Lynch HT, Weitzel JN, de la Chapelle A, Syngal S, Lynch P, Parry S, Jenkins MA, Gallinger S, Holter S, Aronson M, Newcomb PA, Burnett T, Le Marchand L, Pichurin P, Hampel H, Terdiman JP, Lu KH, Thibodeau S, Lindor NM. PMS2 monoallelic mutation carriers: the known unknown. Genet Med. 2016;18:13–9. [PMC free article: PMC4834863] [PubMed: 25856668]
• Gruber SB, Kohlmann W. The genetics of hereditary non-polyposis colorectal cancer. J Natl Compr Canc Netw. 2003;1:137–44. [PubMed: 19764157]
• Guilford PJ, Hopkins JB, Grady WM, Markowitz SD, Willis J, Lynch H, Rajput A, Wiesner GL, Lindor NM, Burgart LJ, Toro TT, Lee D, Limacher JM, Shaw DW, Findlay MP, Reeve AE. E-cadherin germline mutations define an inherited cancer syndrome dominated by diffuse gastric cancer. Hum Mutat. 1999;14:249–55. [PubMed: 10477433]
• Hamilton SR, Liu B, Parsons RE, Papadopoulos N, Jen J, Powell SM, Krush AJ, Berk T, Cohen Z, Tetu B, Burger PC, Wood PA, Taqi F, Booker SV, Petersen GM, Offerhaus GJA, Tersmette AC, Giardiello FM, Vogelstein V, Kinzler KW. The molecular basis of Turcot's syndrome. N Engl J Med. 1995;332:839–47. [PubMed: 7661930]
• Haraldsdottir S, Hampel H, Wei L, Wu C, Frankel W, Bekaii-Saab T, de la Chapelle A, Goldberg RM. Prostate cancer incidence in males with Lynch syndrome. Genet Med. 2014;16:553–7. [PMC free article: PMC4289599] [PubMed: 24434690]
• Hegde M, Ferber M, Mao R, Samowitz W, Ganguly A., Working Group of the American College of Medical Genetics and Genomics (ACMG) Laboratory Quality Assurance Committee. ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis). Genet Med. 2014;16:101–16. [PubMed: 24310308]
• Hendriks YM, Jagmohan-Changur S, van der Klift HM, Morreau H, van Puijenbroek M, Tops C, van Os T, Wagner A, Ausems MG, Gomez E, Breuning MH, Brocker-Vriends AH, Vasen HF, Wijnen JT. Heterozygous mutations in PMS2 cause hereditary nonpolyposis colorectal carcinoma (Lynch syndrome). Gastroenterology. 2006;130:312–22. [PubMed: 16472587]
• Hüneburg R, Lammert F, Rabe C, Rahner N, Kahl P, Büttner R, Propping P, Sauerbruch T, Lamberti C. Chromocolonoscopy detects more adenomas than white light colonoscopy or narrow band imaging colonoscopy in hereditary nonpolyposis colorectal cancer screening. Endoscopy. 2009;41:316–22. [PubMed: 19340735]
• Järvinen HJ, Renkonen-Sinisalo L, Aktán-Collán K, Peltomäki P, Aaltonen LA, Mecklin JP. Ten years after mutation testing for Lynch syndrome: cancer incidence and outcome in mutation-positive and mutation negative family members. J Clin Oncol. 2009;27:4793–7. [PubMed: 19720893]
• Kastrinos F, Mukherjee B, Tayob N, Wang F, Sparr J, Raymond VM, Bandipalliam P, Stoffel EM, Gruber SB, Syngal S. Risk of pancreatic cancer in families with Lynch syndrome. JAMA. 2009;302:1790–5. [PMC free article: PMC4091624] [PubMed: 19861671]
• Kastrinos F, Ojha RP, Leenen C, Alvero C, Mercado RC, Balmaña J, Valenzuela I, Balaguer F, Green R, Lindor NM, Thibodeau SN, Newcomb P, Win AK, Jenkins M, Buchanan DD, Bertario L, Sala P, Hampel H, Syngal S, Steyerberg EW. Lynch syndrome prediction model validation study group. Comparison of prediction models for Lynch syndrome among individuals with colorectal cancer. J Natl Cancer Inst. 2015;108(2) [PMC free article: PMC4862416] [PubMed: 26582061]
• Kastrinos F, Steyerberg EW, Mercado R, Balmana J, Holter S, Gallinger S, Siegnund KD, Church JM, Jenkins MA, Lindor NM, Thibodeau SN, Burbidge LA, Wenstrup RJ, Syngal S. The PREMM(1,2,6) Model predicts risk of MLH1, MSH2, and MSH6 germline mutations. Gastroenterology. 2011;140:73–81. [PMC free article: PMC3125673] [PubMed: 20727894]
• Kawakami H, Zaanan A, Sinicrope FA. Microsatellite instability testing and its role in the management of colorectal cancer. Curr Treat Options Oncol. 2015;16:30. [PMC free article: PMC4594190] [PubMed: 26031544]
• Kempers MJ, Kuiper RP, Ockeloen CW, Chappuis PO, Hutter P, Rahner N, Schackert HK, Steinke V, Holinski-Feder E, Morak M, Kloor M, Büttner R, Verwiel ET, van Krieken JH, Nagtegaal ID, Goossens M, van der Post RS, Niessen RC, Sijmons RH, Kluijt I, Hogervorst FB, Leter EM, Gille JJ, Aalfs CM, Redeker EJ, Hes FJ, Tops CM, van Nesselrooij BP, van Gijn ME, Gómez García EB, Eccles DM, Bunyan DJ, Syngal S, Stoffel EM, Culver JO, Palomares MR, Graham T, Velsher L, Papp J, Oláh E, Chan TL, Leung SY, van Kessel AG, Kiemeney LA, Hoogerbrugge N, Ligtenberg MJ. Risk of colorectal and endometrial cancers in EPCAM deletion-positive Lynch syndrome: a cohort study. Lancet Oncol. 2011;12:49–55. [PMC free article: PMC3670774] [PubMed: 21145788]
• Kowalski LD, Mutch DG, Herzog TJ, Rader JS, Goodfellow PJ. Mutational analysis of MLH1 and MSH2 in 25 prospectively-acquired RER+ endometrial cancers. Genes Chromosomes Cancer. 1997;18:219–27. [PubMed: 9071575]
• Kuiper RP, Vissers LE, Venkatachalam R, Bodmer D, Hoenselaar E, Goossens M, Haufe A, Kamping E, Niessen RC, Hogervorst FB, Gille JJ, Redeker B, Tops CM, van Gijn ME, van den Ouweland AM, Rahner N, Steinke V, Kahl P, Holinski-Feder E, Morak M, Kloor M, Stemmler S, Betz B, Hutter P, Bunyan DJ, Syngal S, Culver JO, Graham T, Chan TL, Nagtegaal ID, van Krieken JH, Schackert HK, Hoogerbrugge N, van Kessel AG, Ligtenberg MJ. Recurrence and variability of germline EPCAM deletions in Lynch syndrome. Hum Mutat. 2011;32:407–14. [PubMed: 21309036]
• Ladabaum U, Wang G, Terdiman J, Blanco A, Kuppermann M, Boland CR, Ford J, Elkin E, Phillips KA. Strategies to identify Lynch syndrome among patients with colorectal cancer: a cost-effectiveness analysis. Ann Intern Med. 2011;155:69–79. [PMC free article: PMC3793257] [PubMed: 21768580]
• Ligtenberg MJL, Kuiper RP, Chan TL, Goossens M, Hebeda KM, Voorendt M, Lee TY, Bodmer D, Hoenselaar E, Hendriks-Cornelissen SJ, Tsui WY, Kong CK, Brunner HG, van Kessel AG, Yuen ST, van Krieken JH, Leung SY, Hoogerbrugge N. Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3' exons of TACSTD1. Nat Genet. 2009;41:112–7. [PubMed: 19098912]
• Lindor NM, Rabe K, Petersen GM, Haile R, Casey G, Baron J, Gallinger S, Bapat B, Aronson M, Hopper J, Jass J, LeMarchand L, Grove J, Potter J, Newcomb P, Terdiman JP, Conrad P, Moslein G, Goldberg R, Ziogas A, Anton-Culver H, de Andrade M, Siegmund K, Thibodeau SN, Boardman LA, Seminara D. Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X. JAMA. 2005;293:1979–85. [PMC free article: PMC2933042] [PubMed: 15855431]
• Lu KH, Dinh M, Kohlmann W, Watson P, Green J, Syngal S, Bandipalliam P, Chen LM, Allen B, Conrad P, Terdiman J, Sun C, Daniels M, Burke T, Gershenson DM, Lynch H, Lynch P, Broaddus RR. Gynecologic cancer as a "sentinel cancer" for women with hereditary nonpolyposis colorectal cancer syndrome. Obstet Gynecol. 2005;105:569–74. [PubMed: 15738026]
• Lu KH, Loose DS, Yates MS, Nogueras-Gonzalez GM, Munsell MF, Chen LM, Lynch H, Cornelison T, Boyd-Rogers S, Rubin M, Daniels MS, Conrad P, Milbourne A, Gershenson DM, Broaddus RR. Prospective multicenter randomized intermediate biomarker study of oral contraceptive versus depo-provera for prevention of endometrial cancer in women with Lynch syndrome. Cancer Prev Res (Phila). 2013;6:774–81. [PMC free article: PMC3737517] [PubMed: 23639481]
• Lu SL, Kawabata M, Imamura T, Akiyama Y, Nomizu T, Miyazono K, Yuasa Y. HNPCC associated with germline mutation in the TGF-beta type II receptor gene. Nat Genet. 1998;19:17–8. [PubMed: 9590282]
• Machin P, Catasus L, Pons C, Munoz J, Conde-Zurita JM, Balmana J, Barnadas M, Marti RM, Prat J, Matias-Guiu X. Microsatellite instability and immunostaining for MSH-2 and MLH-1 in cutaneous and internal tumors from patients with the Muir-Torre syndrome. J Cutan Pathol. 2002;29:415–20. [PubMed: 12139636]
• Mange S, Bellcross C, Cragun D, Duquette D, Gorman L, Hampel H, Jasperson J. Creation of a network to promote universal screening for Lynch syndrome: the Lynch syndrome screening network. J Genet Couns. 2015;24:421–7. [PMC free article: PMC4547789] [PubMed: 25220566]
• Maxwell GL, Risinger JI, Alvarez AA, Barrett JC, Berchuck A. Favorable survival associated with microsatellite instability in endometrioid endometrial cancers. Obstet Gynecol. 2001;97:417–22. [PubMed: 11239648]
• Misago N, Narisawa Y. Sebaceous neoplasms in Muir-Torre syndrome. Am J Dermatopathol. 2000;22:155–61. [PubMed: 10770437]
• Miyaki M, Konishi M, Tanaka K, Kikuchi-Yanoshita R, Muraoka M, Yasuno M, Igari T, Koike M, Chiba M, Mori T. Germline mutation of MSH6 as the cause of hereditary nonpolyposis colorectal cancer. Nat Genet. 1997;17:271–2. [PubMed: 9354786]
• Mork ME, You YN, Ying J, Bannon SA, Lynch PM, Rodriguez-Bigas MA, Vilar E. High prevalence of hereditary cancer syndromes in adolescents and young adults with colorectal cancer. J Clin Oncol. 2015;33:3544–9. [PMC free article: PMC4979241] [PubMed: 26195711]
• Mueller-Koch Y, Vogelsang H, Kopp R, Lohse P, Keller G, Aust D, Muders M, Gross M, Daum J, Schiemann U, Grabowski M, Scholz M, Kerker B, Becker I, Henke G, Holinski-Feder E. Hereditary non-polyposis colorectal cancer: clinical and molecular evidence for a new entity of hereditary colorectal cancer. Gut. 2005;54:1733–40. [PMC free article: PMC1774771] [PubMed: 15955785]
• NCCN. National Comprehensive Cancer Network guidelines for colorectal cancer screening. 2016.
• Nicolaides NC, Carter KC, Shell BK, Papadopoulos N, Vogelstein B, Kinzler KW. Genomic organization of the human PMS2 gene family. Genomics. 1995;30:195–206. [PubMed: 8586419]
• Niessen RC, Hofstra RM, Westers H, Ligtenberg MJ, Kooi K, Jager PO, de Groote ML, Dijkhuizen T, Olderode-Berends MJ, Hollema H, Kleibeuker JH, Sijmons RH. Germline hypermethylation of MLH1 and EPCAM deletions are a frequent cause of Lynch syndrome. Genes Chromosomes Cancer. 2009;48:737–44. [PubMed: 19455606]
• Nilbert M, Therkildsen C, Nissen A, Akerman M, Bernstein I. Sarcomas associated with hereditary nonpolyposis colorectal cancer: broad anatomical and morphological spectrum. Fam Cancer. 2009;8:209–13. [PubMed: 19130300]
• Obermair A, Youlden DR, Young JP, Lindor NM, Baron JA, Newcomb P, Parry S, Hopper JL, Haile R, Jenkins MA. Risk of endometrial cancer for women diagnosed with HNPCC-related colorectal carcinoma. Int J Cancer. 2010;127:2678–84. [PMC free article: PMC2947566] [PubMed: 20533284]
• Pande M, Lynch PM, Hopper JL, Jenkins MA, Gallinger S, Haile RW, LeMarchand L, Lindor NM, Campbell PT, Newcomb PA, Potter JD, Baron JA, Frazier ML, Amos CI. Smoking and colorectal cancer in Lynch syndrome: results from the Colon Cancer Family Registry and the University of Texas M.D. Anderson Cancer Center. Clin Cancer Res. 2010;16:1331–9. [PMC free article: PMC2822883] [PubMed: 20145170]
• Park YJ, Shin KH, Park JG. Risk of gastric cancer in hereditary nonpolyposis colorectal cancer in Korea. Clin Cancer Res. 2000;6:2994–8. [PubMed: 10955776]
• Peltomäki P. Role of DNA mismatch repair defects in the pathogenesis of human cancer. J Clin Oncol. 2003;21:1174–9. [PubMed: 12637487]
• Peltomäki P, Vasen H. Mutations associated with HNPCC predisposition -- Update of ICG-HNPCC/INSiGHT mutation database. Dis Markers. 2004;20:269–76. [PMC free article: PMC3839397] [PubMed: 15528792]
• Ponti G, Losi L, Pedroni M, Lucci-Cordisco E, Di Gregorio C, Pellancani G, Seidenari S. Value of MLH1 and MSH2 mutations in the appearance of Muir-Torre syndrome phenotype in HNPCC patients presenting sebaceous gland tumors or keratoacanthomas. J Invest Dermatol. 2006;126:2302–7. [PubMed: 16826164]
• Pritchard CC, Mateo J, Walsh MF, De Sarkar N, Abida W, Beltran H, Garofalo A, Gulati R, Carreira S, Eeles R, Elemento O, Rubin MA, Robinson D, Lonigro R, Hussain M, Chinnaiyan A, Vinson J, Filipenko J, Garraway L, Taplin ME, AlDubayan S, Han GC, Beightol M, Morrissey C, Nghiem B, Cheng HH, Montgomery B, Walsh T, Casadei S, Berger M, Zhang L, Zehir A, Vijai J, Scher HI, Sawyers C, Schultz N, Kantoff PW, Solit D, Robson M, Van Allen EM, Offit K, de Bono J, Nelson PS. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med. 2016;375:443–53. [PMC free article: PMC4986616] [PubMed: 27433846]
• Rabban JT, Calkins SM, Karnezis AN, Grenert JP, Blanco A, Crawford B, Chen LM. Association of Tumor Morphology With Mismatch-repair Protein Status in Older Endometrial Cancer Patients: Implications for Universal Versus Selective Screening Strategies for Lynch Syndrome. Am J Surg Pathol. 2014;38:793–800. [PubMed: 24503759]
• Rahmi G, Lecomte T, Malka D, Maniere T, Le Rhun M, Guimbaud R, Lapalus MG, Le Sidaner A, Moussata D, Caron O, Barbieux JP, Gaudric M, Coron E, Barange K, Ponchon T, Sautereau D, Samaha E, Saurin JC, Chaussade S, Laurent-Puig P, Chatellier G, Cellier C. Impact of chromoscopy on adenoma detection in patients with Lynch syndrome: a prospective, multicenter, blinded, tandem colonoscopy study. Am J Gastroenterol. 2015;110:288–98. [PubMed: 25601014]
• Raymond VM, Everett JN, Furtado LV, Gustafson SL, Jungbluth CR, Gruber SB, Hammer GD, Stoffel EM, Greenson JK, Giordano TJ, Else T. Adrenocortical carcinoma is a lynch syndrome-associated cancer. J Clin Oncol. 2013a;31:3012–8. [PMC free article: PMC3739861] [PubMed: 23752102]
• Raymond VM, Mukherjee B, Wang F, Huang SC, Stoffel EM, Kastrinos F, Syngal S, Cooney KA, Gruber SB. Elevated risk of prostate cancer among men with Lynch syndrome. J Clin Oncol. 2013b;31:1713–8. [PMC free article: PMC3641694] [PubMed: 23530095]
• Renkonen-Sinisalo L, Sipponen P, Aarnio M, Julkunen R, Aaltonen LA, Sarna S, Jarvinen HJ, Mecklin JP. No support for endoscopic surveillance for gastric cancer in hereditary non-polyposis colorectal cancer. Scand J Gastroenterol. 2002;37:574–7. [PubMed: 12059060]
• Rodriguez-Bigas MA, Vasen HF, Lynch HT, Watson P, Myrhoj T, Jarvinen HJ, Mecklin JP, Macrae F, St John DJ, Bertario L, Fidalgo P, Madlensky L, Rozen P. Characteristics of small bowel carcinoma in hereditary nonpolyposis colorectal carcinoma. International Collaborative Group on HNPCC. Cancer. 1998;83:240–4. [PubMed: 9669805]
• Rothwell PM, Fowkes FG, Belch JF, Ogawa H, Warlow CP, Meade TW. Effect of daily aspirin on long-term randomized trials. Lancet. 2011;377:31–41. [PubMed: 21144578]
• Ryan S, Jenkins MA, Win AK. Risk of prostate cancer in Lynch syndrome: a systematic review and meta-analysis. Cancer Epidemiol Biomarkers Prev. 2014;23:437–49. [PubMed: 24425144]
• Schulmann K, Brasch FE, Kunstmann E, Engel C, Pagenstecher C, Vogelsang H, Kruger S, Vogel T, Knaebel HP, Ruschoff J, Hahn SA, Knebel-Doeberitz MV, Moeslein G, Meltzer SJ, Schackert HK, Tympner C, Mangold E, Schmiegel W. HNPCC-associated small bowel cancer: clinical and molecular characteristics. Gastroenterology. 2005;128:590–9. [PubMed: 15765394]
• Senter L, Clendenning M, Sotamaa K, Hampel H, Green J, Potter JD, Lindblom A, Lagerstedt K, Thibodeau SN, Lindor NM, Young J, Winship I, Dowty JG, White DM, Hopper JL, Baglietto L, Jenkins MA, de la Chapelle A. The clinical phenotype of Lynch syndrome due to germline PMS2 mutations. Gastroenterology. 2008;135:419–28. [PMC free article: PMC2759321] [PubMed: 18602922]
• Sijmons R, Hofstra R, Hollema H, Mensink R, van der Hout A, Hoekstra H, Kleibeuker J, Molenaar W, Wijnen J, Fodde R, Vasen H, Buys C. Inclusion of malignant fibrous histiocytoma in the tumour spectrum associated with hereditary non-polyposis colorectal cancer. Genes Chromosomes Cancer. 2000;29:353–5. [PubMed: 11066081]
• Sivagnanam M, Schaible T, Szigeti R, Byrd RH, Finegold MJ, Ranganathan S, Gopalakrishna GS, Tatevian N, Kellermayer R. Further evidence for EpCAM as the gene for congenital tufting enteropathy. Am J Med Genet. 2010;152A:222–4. [PubMed: 20034091]
• Smith MJ, Urquhart JE, Harkness EF, Miles EK, Bowers NL, Byers HJ, Bulman M, Gokhale C, Wallace AJ, Newman WG, Evans DG. The Contribution of Whole Gene Deletions and Large Rearrangements to the Mutation Spectrum in Inherited Tumor Predisposing Syndromes. Hum Mutat. 2016;37:250–6. [PubMed: 26615784]
• South CD, Hampel H, Comeras I, Westman JA, Frankel WL, de la Chapelle A. The frequency of Muir-Torre syndrome among Lynch syndrome families. J Natl Cancer Inst. 2008;100:277–81. [PubMed: 18270343]
• Stoffel EM, Turgeon DK, Stockwell DH, Zhao L, Normolle DP, Tuck MK, Bresalier RS, Marcon NE, Baron JA, Ruffin MT, Brenner DE, Syngal S., Great Lakes-New England Clinical Epidemiology and Validation Center of the Early Detection Research Network. Missed adenomas during colonoscopic surveillance in individuals with Lynch Syndrome (hereditary nonpolyposis colorectal cancer). Cancer Prev Res (Phila). 2008;1:470–5. [PMC free article: PMC2671076] [PubMed: 19138994]
• Suzui M, Yoshimi N, Hara A, Morishita Y, Tanaka T, Mori H. Genetic alterations in a patient with Turcot's syndrome. Pathol Int. 1998;48:126–33. [PubMed: 9589476]
• Tutlewska K, Lubinski J, Kurzawski G. Germlie deletions in the EPCAM gene as a cause of Lynch syndrome. Hered Cancer Clin Pract. 2013;11:9. [PMC free article: PMC3765447] [PubMed: 23938213]
• van der Klift HM, Tops CM, Bik EC, Boogaard MW, Borgstein AM, Hansson KB, Ausems MG, Gomez Garcia E, Green A, Hes FJ, Izatt L, van Hest LP, Alonso AM, Vriends AH, Wagner A, van Zelst-Stams WA, Vasen HF, Morreau H, Devilee P, Wijnen JT. Quantification of sequence exchange events between PMS2 and PMS2CL provides a basis for improved mutation scanning of Lynch syndrome patients. Hum Mutat. 2010;31:578–87. [PubMed: 20186688]
• van der Klift H, Wijnen J, Wagner A, Verkuilen P, Tops C, Otway R, Kohonen-Corish M, Vasen H, Oliani C, Barana D, Moller P, Delozier-Blanchet C, Hutter P, Foulkes W, Lynch H, Burn J, Moslein G, Fodde R. Molecular characterization of the spectrum of genomic deletions in the mismatch repair genes MSH2, MLH1, MSH6, and PMS2 responsible for hereditary nonpolyposis colorectal cancer (HNPCC). Genes Chromosomes Cancer. 2005;44:123–38. [PubMed: 15942939]
• van der Post RS, Kiemeny LA, Ligtenberg MJ, Witjes JA, Hulsbergen-van de Kaa CA, Bodmer D, Schaap L, Kets CM, van Krieken JH, Hoogerbrugge N. Risk of urothelial bladder cancer in Lynch syndrome is increased, in particular among MSH2 mutation carriers. J Med Genet. 2010;47:464–70. [PMC free article: PMC2991077] [PubMed: 20591884]
• Vasen HFA, Blanco I, Aktan-Collan K, Gopie JP, Alonso A, Aretz S, Bernstein I, Bertario L, Burn J, Capella G, Colas C, Engel C, Frayling IM, Genuardi M, Heinimann K, Hes FJ, Hodgson SV, Karagiannis JA, Lalloo F, Lindblom A, Mecklin JP, Møller P, Myrhoj T, Nagengast FM, Parc Y, Ponz de Leon M, Renkonen-Sinisalo L, Sampson JR, Stormorken A, Sijmons RH, Tejpar S, Thomas HJ, Rahner N, Wijnen JT, Järvinen HJ, Möslein G., Mallorca group. Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts. Gut. 2013;62:812–23. [PMC free article: PMC3647358] [PubMed: 23408351]
• Vaughn CP, Hart KJ, Samowitz WS, Swensen JJ. Avoidance of pseudogene interfence in the detection of 3' deletions in PMS2. Hum Mutat. 2011;32:1063–71. [PubMed: 21618646]
• Vaughn CP, Robles J, Swensen JJ, Miller CE, Lyon E, Mao R, Bayrak-Toydemir P, Samowitz WS. Clinical analysis of PMS2: mutation detection and avoidance of pseudogenes. Hum Mutat. 2010;31:588–93. [PubMed: 20205264]
• Watson P, Butzow R, Lynch HT, Mecklin JP, Jarvinen HJ, Vasen HF, Madlensky L, Fidalgo P, Bernstein I. The clinical features of ovarian cancer in hereditary nonpolyposis colorectal cancer. Gynecol Oncol. 2001;82:223–8. [PubMed: 11531271]
• Watson P, Vasen HF, Mecklin JP, Bernstein I, Aarnio M, Järvinen HJ, Myrhøj T, Sunde L, Wijnen JT, Lynch HT. The risk of extra-colonic, extra-endometrial cancer in the Lynch syndrome. Int J Cancer. 2008;123:444–9. [PMC free article: PMC2627772] [PubMed: 18398828]
• Weren RD, Ligteberg MJ, Geurts van Kessel A, De Voer RM, Hoogerbrugge N, Kuiper RP. NTHL1 and MUTYH polyposis syndromes: two sides of the same coin? J Pathol. 2018;244:135–42. [PubMed: 29105096]
• Wimmer K. Relationship between NF1 and constitutive mismatch repair deficiency. In Upadhyaya M, Cooper DN, eds. Neurofibromatosis Type 1. Berlin, Germany: Springer-Verlag; 2012:235-51.
• Wimmer K, Etzler J. Constitutional mismatch repair-deficiency syndrome: have we so far seen only the tip of an iceberg? Hum Genet. 2008;124:105–22. [PubMed: 18709565]
• Win AK, Macinnis RJ, Dowty JG, Jenkins MA. Criteria and prediction models for mismatch repair gene mutations: a review. J Med Genet. 2013a;50:785–93. [PubMed: 23956446]
• Win AK, Young JP, Lindor NM, Tucker KM, Ahnen DJ, Young GP, Buchanan DD, Clendenning M, Giles GG, Winship I, Macrae FA, Goldblatt J, Southey MC, Arnold J, Thibodeau SN, Gunawardena SR, Bapat B, Baron JA, Casey G, Gallinger S, Le Marchand L, Newcomb PA, Haile RW, Hopper JL, Jenkins MA. Colorectal and other cancer risks for carriers and noncarriers from families with a DNA mismatch repair gene mutation: a prospective cohort study. J Clin Oncol. 2012;30:958–64. [PMC free article: PMC3341109] [PubMed: 22331944]
• Win KW, Lindor NM, Jenkins MA. Risk of breast cancer in Lynch syndrome: a systematic review. Breast Cancer Research. 2013b;15:R27. Available online. Accessed 7-24-18. [PMC free article: PMC3672741] [PubMed: 23510156]
• Wu Y, Berends MJ, Mensink RG, Kempinga C, Sijmons RH, van Der Zee AG, Hollema H, Kleibeuker JH, Buys CH, Hofstra RM. Association of hereditary nonpolyposis colorectal cancer-related tumors displaying low microsatellite instability with MSH6 germline mutations. Am J Hum Genet. 1999;65:1291–8. [PMC free article: PMC1288281] [PubMed: 10521294]
• Yurgelun MB, Kulke MH, Fuchs CS, Allen BA, Uno H, Hornick JL, Ukaegbu CI, Brais LK, McNamara PG, Mayer RJ, Schrag D, Meyerhardt JA, Ng K, Kidd J, Singh N, Hartman AR, Wenstrup RJ, Syngal S. Cancer susceptibility gene mutations in individuals with colorectal cancer. J Clin Oncol. 2017;35:1086–95. [PMC free article: PMC5455355] [PubMed: 28135145]

Suggested Reading

• Hampel H, Panescu J, Lockman J, Sotamaa K, Fix D, Comeras I, LaJeunesse J, Nakagawa H, Westman JA, Prior TW, Clendenning M, de la Chapelle A, Frankel W, Penzone P, Cohn DE, Copeland L, Eaton L, Fowler J, Lombardi J, Dunn P, Bell J, Reid G, Lewandowski G, Vaccarello L. Comment on: Screening for Lynch syndrome (hereditary nonpolyposis colorectal cancer) among endometrial cancer patients. Cancer Res. 2007;67:9603. [PubMed: 17909073]
• Rumilla K, Schowalter KV, Lindo NM, Thomas BC, Mensink KA, Gallinger S, Holter S, Newcomb PA, Potter JD, Jenkins MA, Hopper JL, Long TI, Weisenberger DJ, Haile RW, Casey G, Laird PW, Le Marchand L, Thibodeau SN. Frequency of deletions of EPCAM (TACSTD1) in MSH2-associated Lynch syndrome cases. J Mol Diagn. 2011;13:93–9. [PMC free article: PMC3069927] [PubMed: 21227399]

Revision History

• 12 April 2018 (sw) Revision: Tumor testing table (2) added
• 1 February 2018 (sw) Comprehensive update posted live
• 22 May 2014 (me) Comprehensive update posted live
• 20 September 2012 (cd) Revision: Multigene panels for Lynch syndrome (hereditary non-polyposis colon cancer) available clinically
• 11 August 2011 (me) Comprehensive update posted live
• 29 November 2006 (me) Comprehensive update posted live
• 5 February 2004 (me) Review posted live
• 18 April 2003 (sg) Original submission