Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group
In 2009, the EGAPP Working Group recommended (EGAPP, 2009):

1. Offering genetic testing for Lynch Syndrome to individuals with newly diagnosed colorectal cancer to reduce morbidity and mortality in relatives. However, they do not recommend a specific testing protocol.
2. That individuals with newly diagnosed CRC should be routinely offered counseling and educational materials aimed at informing them and their relatives of the potential benefits and harms associated with genetic testing to identify Lynch Syndrome.  
3. “Microsatellite instability (MSI) testing or immunohistochemical (IHC) testing (with or without BRAF mutation testing) of the tumor tissue are examples of preliminary testing strategies that could be used to select patients for subsequent diagnostic testing. Diagnostic testing involves MMR gene mutation (and deletion/duplication) testing of the proband, usually using a blood sample. Lynch syndrome is most commonly caused by mutations in the two MMR genes MLH1 and MSH2; less commonly by mutations in MSH6 and PMS2.”

The EGAPP was launched by the CDC Office of Public Health Genomics in 2004. EGAPP’s website, which includes the 2009 Lynch Syndrome guidelines, states that the page is archived and is no longer being updated (EGAPP, 2016).

National Comprehensive Cancer Network (NCCN)
Genetic/Familial High-Risk Assessment: Colorectal (NCCN, 2022)
The NCCN lists the following criteria for the evaluation of Lynch Syndrome:

• “Known LS pathogenic variant in the family
• An individual with colorectal or endometrial cancer and any of the following:

• Diagnosed < 50 y
• A synchronous or metachronous LS-related cancer regardless of age
• 1 first-degree or second-degree relative with LS-related cancer diagnosed < 50 y
• ≥ 2 first-degree or second-degree relatives with LS-related cancers regardless of age

• Family history of any of the following:
  • ≥ 1 first-degree relative with colorectal or endometrial cancer diagnosed < 50 y
  • ≥ 1 first-degree relative with colorectal or endometr
  • ≥ 2 first-degree or second-degree relatives with LS-related cancer, including ≥ 1 diagnosed < 50 y
  • ≥ 3 first-degree or second-degree relatives with LS-related cancers regardless of age
• Increased model-predicted risk for Lynch Syndrome
• An individual with a ≥ 5% risk of having an MMR gene pathogenic variant based on predictive models (i.e., PREMM5, MMRpro, MMRpredict)
  • Individuals with a personal history of colorectal and/or endometrial cancer with a PREMM5 score of ≥ 2.5% should be considered for multi-gene panel testing.
  • For individuals without a personal history of colorectal cancer and/or endometrial cancer, some data have suggested using a PREMM5 score threshold of ≥ 2.5% rather than ≥ 5% to select individuals for MMR genetic testing. Based on these data, it is reasonable for testing to be done based on the ≥ 2.5% score result and clinical judgment. Of note, with the lower threshold, there is an increase in sensitivity, but a decrease in specificity.”

• Personal history of a tumor with MMR deficiency determined by PCR, NGS, or IHC diagnosed at any age

The NCCN considers LS-related cancers to “include colorectal, endometrial, gastric, ovarian, pancreas, urothelial, brain (usually glioblastoma), biliary tract, and small intestinal cancers, as well as sebaceous adenomas, sebaceous carcinomas, and keratoacanthomas as seen in Muir-Torre syndrome.”

The NCCN also states the following: “The panel recommends tumor screening for MMR deficiency for all colorectal and endometrial cancers regardless of age at diagnosis. Tumor screening for CRCs for MMR deficiencies for purposes of screening of LS is not required if MGPT is chosen as the strategy for screening for LS but may still be required for CRC therapy selection. Consider tumor screening for MMR deficiency for sebaceous neoplasms as well as the following adenocarcinomas: small bowel, gastric, pancreas, biliary tract, brain, bladder, urothelial, and adrenocortical cancers regardless of age at diagnosis. Direct referral for germline testing to rule out LS may be preferred in patients with a strong family history or if diagnosed age < 50 y, … MSI-H, or loss of MMR protein expression.”

In the section of the guidelines titled “Strategies for Evaluating for Lynch syndrome in Individuals Meeting Criteria for the Evaluation of Lynch Syndrome,” it is recommended that when a deleterious Lynch syndrome pathogenic variant in a family is known, “the individual should be tested for the familial pathogenic variant.” Moreover, the guidelines recommend that genetic testing should also be offered to at-risk family members.

When no Lynch syndrome pathogenic variant is present in proband or in family, individuals should first refer to the Amsterdam and Bethesda criteria. However, overall, “for individuals without a previously known Lynch syndrome the panel recommends additional evaluation for Lynch syndrome based on clinical criteria, including for individuals with no known Lynch syndrome pathogenic variant who meet the Amsterdam II criteria or Bethesda Guidelines, have a cancer diagnosis prior to age 50 years, or have predicted risk for Lynch syndrome >5% on one of the following prediction models: MMRpro, PREMM5, or MMRpredict.” However, due to issues of suboptimal sensitivity of clinical criteria when it comes to identifying individuals with Lynch syndrome, “the panel recommends universal screening of all CRCs, and endometrial cancers to maximize sensitivity for identifying individuals with Lynch syndrome (LS) and to simplify care processes.”

In terms of initial tumor testing methodologies, “the panel recommends using only one test [either MSI or IHC testing] initially” and only “If normal results are found and Lynch syndrome is strongly suspected” that the other test be employed. Moreover, “Where genetic testing is recommended, the panel recommends consultation with an individual with expertise in genetics, and germline testing to exclude presence of Lynch-associated mutations.

The (NCCN, 2022) does not recommend multi-gene testing in the following situations:

1. When “there is an individual from a family with a known mutation and there is no other reason for multi-gene testing;
2. the patient’s family history is strongly suggestive of a known hereditary syndrome; and
3. the patient is diagnosed with CRC with MSI or loss of one or more DNA MMR proteins

In the above three scenarios, syndrome-specific panels may be considered.”

“Multigene testing may be considered (but may not be limited based on clinical judgment) in the following scenarios:

• A patient with a personal or family history that meets criteria for more than one hereditary cancer syndrome (e.g., Lynch syndrome and BRCA-related breast and/or ovarian cancer)
• Colonic polyposis with uncertain histology
• Adenomatous polyposis (specific to APC, MUTYH, GREM1, NTHL1, POLE, and POLD1)
• Family history does not meet criteria for established testing guidelines but there is suspicion of hereditary cancer, and an appropriate panel is available
• Family history is limited or unknown, but patient has concerns about hereditary cancer
• As second-line testing when first-line testing is inconclusive” (NCCN, 2022).

National Institute for Health and Care Excellence (NICE)
NICE, in 2017, released their guidelines concerning molecular testing for LS in people with CRC. The recommend the following (NICE, 2017):

• “Offer testing to all people with colorectal cancer, when first diagnosed, using immunohistochemistry for mismatch repair proteins or microsatellite instability testing to identify tumours with deficient DNA mismatch repair, and to guide further sequential testing for Lynch syndrome, ... Do not wait for the results before starting treatment.
• “If using immunohistochemistry, follow the steps in Table 1.”

• “If using microsatellite instability testing, follow the steps in Table 2.”

• “Healthcare professionals should ensure that people are informed of the possible implications of test results for both themselves and their relatives, and ensure that relevant support and information is available. Discussion of genetic testing should be done by a healthcare professional with appropriate training” (NICE, 2017).

The NICE published new recommendations dealing with testing strategies for Lynch syndrome in people with endometrial cancer in 2020 (NICE, 2020). Said recommendations are provided below:

“1.1 Offer testing for Lynch syndrome to people who are diagnosed with endometrial cancer. Use immunohistochemistry (IHC) to identify tumours with mismatch repair (MMR) deficiency:

• If IHC is abnormal with loss of MLH1, or loss of both MLH1 and PMS2 protein expression, do MLH1 promoter hypermethylation testing of tumour DNA. If MLH1 promoter hypermethylation is not detected, offer germline genetic testing to confirm Lynch syndrome.
• If IHC is abnormal with loss of MSH2, MSH6 or isolated PMS2 protein expression, offer germline genetic testing to confirm Lynch syndrome.

1.2  Healthcare professionals should inform people about the possible implications of test results for both themselves and their relatives, and give support and information. Discussion of genetic testing and obtaining consent should be done by a healthcare professional with appropriate training.

1.3  Laboratories doing IHC for MMR proteins, MLH1 promoter hypermethylation testing or germline genetic testing should take part in a recognised external quality assurance programme.”

In February 2022, NICE updated one of their quality statements to recommend that  adults with a new diagnosis of colorectal cancer be tested for Lynch syndrome. NICE recommends offering of cascade testing to family members in addition to testing individuals newly diagnosed with colorectal cancer. NICE suggests the following laboratory testing: “IHC for mismatch repair proteins or microsatellite instability testing, BRAF V600E testing and MLH1 promoter hypermethylation testing …” According to their statement, these tests should be a part of the “standard pathology report requested by oncology,” and lab providers should “ensure that laboratory protocols are in place to provide genetic testing of germline DNA for Lynch syndrome in adults with a new diagnosis of colorectal cancer and in whom test results are suggestive of Lynch syndrome”(NICE, 2022).

American Society of Clinical Oncology (ASCO)
The American Society of Clinical Oncology (ASCO) recommends that “genetic testing only be conducted in the setting of pre- and post-test counseling” (Robson et al., 2010). In 2015, ASCO stated that “identifying inherited mutations in genes such as BRCA1, BRCA2, and the genes associated with Lynch syndrome allows for interventions that can significantly reduce the development of cancer and improve survival. Targeted capture assays employing NGS [next generation sequencing] technology allow for testing many genes simultaneously, including genes that would not necessarily have been tested using the phenotype-directed approach, as well as genes of less clearly established clinical utility” (Robson et al., 2015). According to ASCO, multi-gene panel testing is particularly useful in situations where there are multiple high-penetrance genes associated with a specific cancer, and “one example of such a situation is Lynch syndrome, when the results of immunohistochemical analysis are not available to direct testing” (Robson et al., 2015).

U.S. Multi-Society Task Force on Colorectal Cancer
n 2014, The U.S. Multi-Society Task Force published the following guidelines on Colorectal Cancer (Giardiello et al., 2014):

“Testing for MMR deficiency of newly diagnosed CRC should be performed. This can be done for all CRCs, or CRC diagnosed at age 70 years or younger, and in individuals older than 70 years who have a family history concerning for LS. Analysis can be done by IHC testing for the MLH1/MSH2/MSH6/PMS2 proteins and/or testing for MSI. Tumors that demonstrate loss of MLH1 should undergo BRAF testing or analysis of MLH1 promoter hypermethylation.” Also, “Individuals who have a personal history of a tumor showing evidence of MMR deficiency (without evidence of MLH1 promoter methylation); uterine cancer diagnosed at younger than age 50 years; a known family MMR gene mutation; fulfill Amsterdam criteria or revised Bethesda guidelines; and/or have a personal risk of ≥5% chance of LS based on prediction models should undergo genetic evaluation for LS.”

Updated 2017 guidelines from the U.S. Multi-Society Task Force give the following guideline for colorectal cancer screening and LS (Rex et al., 2017):

• “colonoscopy is recommended at 10-year intervals in average-risk persons and at 1- to 2-year intervals in those with Lynch syndrome.”

However, for specific LS related screening techniques and recommendations, the updated 2017 article states that the Giardiello et al. (2014) guidelines are still the most current.

In 2022, the U.S. Multi-Society Task Force published updated guidelines on colorectal cancer (Patel et al., 2022). One of the recommendations was that “average-risk CRC screening” start at age 45 on a qualified basis because of the increasing incidence and mortality from colorectal cancer. However, this task force update did not mention Lynch syndrome specifically.

American Society for Clinical Pathology (ASCP), College of American Pathologists (CAP), Association for Molecular Pathology (AMP), and American Society of Clinical Oncology (ASCO)
The ASCP, CAP, AMP, and ASCO issued guidelines in 2017 stating “BRAF p.V600 mutational analysis should be performed in deficient MMR tumors with loss of MLH1 to evaluate for Lynch Syndrome risk. Presence of a BRAF mutation strongly favors a sporadic pathogenesis. The absence of BRAF mutation does not exclude risk of Lynch syndrome.” In addition, they have added the following recommendation for clinicians: “clinicians should order mismatch repair status testing in patients with colorectal cancers for the identification of patients at high risk for Lynch syndrome and/or prognostic stratification” (Sepulveda et al., 2017).

American College of Gastroenterology (ACG)
In 2015, ACG issued the following practice guidelines for the management of patients with hereditary gastrointestinal cancer syndromes (Syngal et al., 2015):

• “All newly diagnosed colorectal cancers should be evaluated for mismatch repair deficiency.
• Analysis may be done by immunohistochemical (IHC) testing for the MLH1/MSH2/MSH6/PMS2 proteins and/or testing for microsatellite instability; tumors that demonstrate loss of MLH1 should undergo BRAF testing or analysis for MLH1 promoter hypermethylation.
• Individuals who have a personal history of a tumor showing evidence of mismatch repair deficiency (and no demonstrated BRAF mutation or hypermethylation of MLH1), a known family mutation associated with LS, or a risk of ≥5% chance of LS based on risk prediction models should undergo genetic evaluation for LS.
• Genetic testing of patients with suspected LS should include germline mutation genetic testing for the MLH1, MSH2, MSH6, PMS2, and/or EPCAM genes or the altered gene(s) indicated by IHC testing.”

American Society of Colon and Rectal Surgeons
The American Society of Colon and Rectal Surgeons (Herzig et al., 2017) published guidelines which recommend (based on 2014 U.S. Multi-Society Task Force on Colorectal Cancer):

“Universal testing (tumor testing):

• Testing for MMR deficiency of newly diagnosed CRC should be performed
• This can be done for all CRCs or CRC diagnosed at age ≤ 70 y and in individuals > 70 y who have a family history concerning for LS
• Analysis can be done by IHC testing for the MLH1/MSH2/MSH6/PMS2 proteins and/or testing for MSI
• Tumors that demonstrate loss of MLH1 should undergo BRAF testing or analysis of MLH1 promoter hypermethylation
• To facilitate surgical planning, tumor testing on suspected CRC should be performed on preoperative biopsy specimens, if possible

Traditional testing (germline testing):

• Individuals who have a personal history of a Lynch syndrome-related tumor showing evidence of MMR deficiency (without evidence of MLH1 promoter methylation)
• Personal history of uterine cancer diagnosed at age < 50 y
• A known family MMR gene mutation
• Fulfill Amsterdam criteria or revised Bethesda guidelines
• Have a personal risk of ≥ 5% chance of LS based on prediction models”

Spanish Society of Medical Oncology (SEOM)
The SEOM published guidelines on hereditary colorectal cancer. These guidelines include the following recommendations:

• “Different screening strategies for LS of all newly diagnosed CRC and EC [endometrial cancers] can be considered including tumor tests for defective MMR function and/or high-level MSI and/or NGS tumor sequencing including BRAF.
• In case of lack of expression of MLH1 and PMS2 by immunohistochemistry, BRAFV600E mutation and/or MLH1 promoter hypermethylation should be carried out to rule out sporadic cases.
• Patients with molecular profiles compatible with LS should be referred to GCU for appropriate counseling and NGS germline genetic testing.
• In families with fulfillment of rBC or a ≥ 2.5% likelihood of LS on the PREMM5 prediction model, prevalent and/or previous CRC and/or EC should follow the same screening procedure before considering referral to GCU (evidence level B, strength 1).
• Multigene panel testing for hereditary CRC and polyposis should include the genes:
  • APC, BMPR1A, EPCAM, MLH1, MSH2, MSH6, MUTYH, PMS2, PTEN, SMAD4 and STK11 (evidence level A, strength 1).
  • AXIN2, BLM, GREM1, NTHL1, POLD1, POLE and TP53 (evidence level B, strength 2).
• Criteria for referral to a GCU and APC/MUTYH or multigene panel testing (evidence level B, strength 1):
  • Patients with > 10 synchronous adenomatous colonic polyps histologically confirmed.
  • Family history of adenomatous colonic polyps (> 10 in > 1 relative), at young age and extracolonic manifestations.
  • Gastric polyps (> 100), in body and fundus, preponderantly fundic glands polyps. Proton pump inhibitor use must be excluded.
  • Consider in: hepatoblastoma, desmoid tumor, cribriform-morular variant of papillary thyroid carcinoma, multifocal or bilateral congenital hypertrophy of retinal pigmented epithelium.
  • Known familial mutation in at-risk relatives” (Guillen-Ponce et al., 2020).

National Society of Genetic Counselors (NSGC) and the Collaborative Group of the Americas on Inherited Colorectal Cancer (Weissman et al., 2012)
The following guidelines were provided by the NSGC and the Collaborative Group of the Americas on Inherited Colorectal Cancer:

• “Microsatellite instability (MSI) and immunohistochemistry (IHC) tumor analyses should be performed on CRC or endometrial cancers as the first‐line testing strategy for any patient being evaluated for LS (this includes individuals with CRC or endometrial cancer who meet Amsterdam I or II criteria or Bethesda guidelines).
• MLH1 promoter methylation and BRAF V600E mutation testing may help to reduce the number of germline genetic tests needed when IHC reveals absence of MLH1 and PMS2. However, NSGC and the CGA‐ICC did not find enough data to recommend one test over the other or both concomitantly.
• IHC may occasionally yield atypical results. If IHC reveals absent MLH1 or MSH2 only, consider genetic testing of those genes individually. If IHC reveals loss of more than two MMR proteins, consider repeating the IHC analysis. If the results persist or if repeat testing was not performed, consider following the algorithm based on the most likely true results (i.e., if MSH2, MSH6 and MLH1 or PMS2 are all absent, follow the loss of MSH2/MSH6 pathway; if MLH1, PMS2 and MSH6 or MSH2 are all absent, follow the MLH1 and PMS2 pathway). Further, it is worth noting that there is a mononucleotide microsatellite in MSH6 that may cause loss of MSH6 with another MMR germline mutation leading to aberrant IHC staining patterns
• When MSI testing is stable, but IHC shows absence of one or more MMR proteins, clinical judgment should be used to determine whether tumor studies should be repeated or germline genetic testing should be pursued
• MSI testing should include, at a minimum, the five markers included in the NCI panel
• While we recognize that some third party payers may not cover MSI and/or IHC analyses on the tumor of a patient's family member(s) (e.g., the family member is deceased), in our expert opinion, we deem testing the family member(s)’ tumor is justified because: 1) LS is one of a few hereditary cancer syndromes that has a validated screening test to determine if germline genetic testing is warranted; 2) if an affected family member is living, it is likely that MSI and IHC will be covered by that relative's insurance; 3) a negative germline genetic test for all four MMR genes in an unaffected patient is uninformative; 4) the cost of direct germline genetic testing for each MMR gene ranges from $1,000 to $1,500, whereas the cost of MSI and IHC together is ~ $1,000; 5) if IHC is abnormal, additional tumor tests (BRAF and MLH1 promoter methylation) may help determine if germline genetic testing is necessary and if it is warranted, testing can be targeted to one or two genes limiting overall costs; and 6) normal MSI and IHC results on an affected individual would significantly lower the likelihood that LS is the explanation for the cancer in the family and germline genetic testing would most likely not be needed.
• Direct germline genetic testing (refers to both DNA sequencing and a technology that detects large rearrangements, insertions, deletions and duplications) may be considered on an affected or unaffected patient being evaluated for LS when MSI and IHC testing are not feasible.
  • In the event that a tumor block is not available, a family member(s) is not willing or able to participate in testing, there are financial concerns or there is insufficient tissue to do either MSI or IHC testing, when indicated (e.g., high familial risk is present such as Amsterdam criteria), direct germline genetic testing may be considered. It should be noted, however, that negative germline testing in an affected individual who has not had MMR IHC can also be uninformative because there are some individuals with unidentifiable MMR gene mutations that would be followed as having LS based on abnormal IHC” (Weissman et al., 2012).

European Society for Medical Oncology (ESMO)
The ESMO published guidelines in 2015 for familial risk-colorectal cancer. The ASCO has endorsed these guidelines, with minor modifications.

The ASCO endorsement panel has “determined that the recommendations of the ESMO guideline are clear, thorough, and based on the most relevant scientific evidence” (ASCO, 2014). The ASCO endorsed the ESMO guidelines (below) with a few minor qualifying statements (in bold):

• “Tumor testing for DNA mismatch repair (MMR) deficiency with immunohistochemistry for MMR proteins and/or MSI should be assessed in all CRC patients. As an alternate strategy, tumor testing should be carried out in individuals with CRC younger than 70 years, or those older than 70 years who fulfill any of the revised Bethesda guidelines
• If loss of MLH1/PMS2 protein expression is observed in the tumor, analysis of BRAF V600E mutation or analysis of methylation of the MLH1 promoter should be carried out first to rule out a sporadic case. If tumor is MMR deficient and somatic BRAF mutation is not detected or MLH1 promoter methylation is not identified, testing for germline mutations is indicated.
• If loss of any of the other proteins (MSH2, MSH6, PMS2) is observed, germline genetic testing should be carried out for the genes corresponding to the absent proteins (e.g., MSH2, MSH6, EPCAM, PMS2, or MLH1)
• Full germline genetic testing for Lynch syndrome should include DNA sequencing and large rearrangement analysis
• Full germline genetic testing of APC should include DNA sequencing and large rearrangement analysis.

Germline testing of MUTYH can be initiated by screening for the most common mutations (G396D, Y179C) in the white population followed by analysis of the entire gene in heterozygotes. Founder mutations among ethnic groups should be taken into account. For nonwhite individuals, full sequencing of MUTYH should be considered” (Stoffel et al., 2015).

The ESMO published guidelines in 2015 for familial risk-colorectal cancer. The ASCO has endorsed these guidelines, with minor modifications.

The ASCO endorsement panel has “determined that the recommendations of the ESMO guideline are clear, thorough, and based on the most relevant scientific evidence” (ASCO, 2014). The ASCO endorsed the ESMO guidelines (below) with a few minor qualifying statements (in bold):

• “Tumor testing for DNA mismatch repair (MMR) deficiency with immunohistochemistry for MMR proteins and/or MSI should be assessed in all CRC patients. As an alternate strategy, tumor testing should be carried out in individuals with CRC younger than 70 years, or those older than 70 years who fulfill any of the revised Bethesda guidelines
• If loss of MLH1/PMS2 protein expression is observed in the tumor, analysis of BRAF V600E mutation or analysis of methylation of the MLH1 promoter should be carried out first to rule out a sporadic case. If tumor is MMR deficient and somatic BRAF mutation is not detected or MLH1 promoter methylation is not identified, testing for germline mutations is indicated.
• If loss of any of the other proteins (MSH2, MSH6, PMS2) is observed, germline genetic testing should be carried out for the genes corresponding to the absent proteins (e.g., MSH2, MSH6, EPCAM, PMS2, or MLH1).
• Full germline genetic testing for Lynch syndrome should include DNA sequencing and large rearrangement analysis
• Full germline genetic testing of APC should include DNA sequencing and large rearrangement analysis.
• Germline testing of MUTYH can be initiated by screening for the most common mutations (G396D, Y179C) in the white population followed by analysis of the entire gene in heterozygotes. Founder mutations among ethnic groups should be taken into account. For nonwhite individuals, full sequencing of MUTYH should be considered” (Stoffel et al., 2015).

In 2019, the ESMO updated their clinical practice guidelines for hereditary gastrointestional cancers, including those for Lynch syndrome. In this set of recommendations, the ESMO maintains that tumor testing with IHC for MMR proteins and/or MSI is recommended in individuals with CRC and that if loss of MLH1 is observed in the tumor, analysis of BRAF V600E mutation or analysis of the methylation of the MLH1 promoter should be carried out first to rule out a sporadic case. They also maintained that full germline genetic testing should include DNA sequencing and large rearrangement analysis, as in the previous guidelines, but also proposed that for those with Lynch syndrome,

• “Somatic MMR gene testing for patients with unexplained abnormal tumour screening is suggested [III, B]
• Clinical risk can be assessed using Amsterdam criteria II or the revised Bethesda guidelines
• MMR IHC and/or MSI screening, with MLH1 promotor hypermethylation analysis in cases of MLH1 expression loss, is recommended for women with endometrial cancer [III, B]
• Follow-up recommendations in mutation carriers include colonoscopy every 1 – 2 years [III, A], and gynaecological examination (with TV US, CA 125 and endometrial biopsy) on a yearly basis from age 30 to 35 years [IV, C]. In all cases, age of onset in the youngest member of the family is to be considered and surveillance be started 5 years earlier [V, B]. High-quality colonoscopy carried out in dedicated centres is advised [IV, C]. UGI endoscopy surveillance (every 1 – 3 years, from age 30 – 35 years) may be considered in patients at high risk. Prophylactic gynaecological surgery might be an option for female carriers who have completed childbearing or are postmenopausal [IV, C]” (Stjepanovic et al., 2019).

Table of Terminology

References

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18. Kastrinos, F., Ojha, R. P., Leenen, C., Alvero, C., Mercado, R. C., Balmana, J., Valenzuela, I., Balaguer, F., Green, R., Lindor, N. M., Thibodeau, S. N., Newcomb, P., Win, A. K., Jenkins, M., Buchanan, D. D., Bertario, L., Sala, P., Hampel, H., Syngal, S., & Steyerberg, E. W. (2016). Comparison of Prediction Models for Lynch Syndrome Among Individuals With Colorectal Cancer. J Natl Cancer Inst, 108(2). https://doi.org/10.1093/jnci/djv308 
19. Kastrinos, F., Uno, H., & Syngal, S. (2018). Commentary: PREMM5 threshold of 2.5% is recommended to improve identification of PMS2 carriers. Fam Cancer, 17(4), 567. https://doi.org/10.1007/s10689-018-0074-6 
20. Kastrinos, F., Uno, H., Ukaegbu, C., Alvero, C., McFarland, A., Yurgelun, M. B., Kulke, M. H., Schrag, D., Meyerhardt, J. A., Fuchs, C. S., Mayer, R. J., Ng, K., Steyerberg, E. W., & Syngal, S. (2017). Development and Validation of the PREMM5 Model for Comprehensive Risk Assessment of Lynch Syndrome. Journal of Clinical Oncology, 35(19), 2165-2172. https://doi.org/10.1200/JCO.2016.69.6120 
21. Kidambi, T. D., Blanco, A., Myers, M., Conrad, P., Loranger, K., & Terdiman, J. P. (2015). Selective Versus Universal Screening for Lynch Syndrome: A Six-Year Clinical Experience. Dig Dis Sci, 60(8), 2463-2469. https://doi.org/10.1007/s10620-014-3234-z 
22. Laish, I., Goldberg, Y., Friedman, E., Kedar, I., Katz, L., Levi, Z., Gingold-Belfer, R., Kopylov, U., Feldman, D., Levi-Reznick, G., & Half, E. (2021). Genetic testing for assessment of lynch syndrome in young patients with polyps. Dig Liver Dis, 53(12), 1640-1646. https://doi.org/10.1016/j.dld.2021.05.031 
23. Lee, S. Y., Kim, D. W., Shin, Y. K., Ihn, M. H., Lee, S. M., Oh, H. K., Ku, J. L., Jeong, S. Y., Lee, J. B., Ahn, S., Won, S., & Kang, S. B. (2016). Validation of Prediction Models for Mismatch Repair Gene Mutations in Koreans. Cancer Res Treat, 48(2), 668-675. https://doi.org/10.4143/crt.2014.288 
24. Ligtenberg, M. J., Kuiper, R. P., Chan, T. L., Goossens, M., Hebeda, K. M., Voorendt, M., Lee, T. Y., Bodmer, D., Hoenselaar, E., Hendriks-Cornelissen, S. J., Tsui, W. Y., Kong, C. K., Brunner, H. G., van Kessel, A. G., Yuen, S. T., van Krieken, J. H., Leung, S. Y., & Hoogerbrugge, N. (2009). Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3' exons of TACSTD1. Nat Genet, 41(1), 112-117. https://doi.org/10.1038/ng.283 
25. Lynch, H. T., Lynch, P. M., Lanspa, S. J., Snyder, C. L., Lynch, J. F., & Boland, C. R. (2009). Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications. Clin Genet, 76(1), 1-18. https://doi.org/10.1111/j.1399-0004.2009.01230.x 
26. Mercado, R. C., Hampel, H., Kastrinos, F., Steyerberg, E., Balmana, J., Stoffel, E., Cohn, D. E., Backes, F. J., Hopper, J. L., Jenkins, M. A., Lindor, N. M., Casey, G., Haile, R., Madhavan, S., de la Chapelle, A., & Syngal, S. (2012). Performance of PREMM(1,2,6), MMRpredict, and MMRpro in detecting Lynch syndrome among endometrial cancer cases. Genet Med, 14(7), 670-680. https://doi.org/10.1038/gim.2012.18 
27. Moreira, L., Balaguer, F., Lindor, N., de la Chapelle, A., Hampel, H., Aaltonen, L. A., Hopper, J. L., Le Marchand, L., Gallinger, S., Newcomb, P. A., Haile, R., Thibodeau, S. N., Gunawardena, S., Jenkins, M. A., Buchanan, D. D., Potter, J. D., Baron, J. A., Ahnen, D. J., Moreno, V., . . . Castells, A. (2012). Identification of Lynch syndrome among patients with colorectal cancer. Jama, 308(15), 1555-1565. https://doi.org/10.1001/jama.2012.13088 
28. MRC. (2014, 09/24/2014). Prediction of DNA mismatch repair gene mutation status in incident colorectal cancer cases. http://hnpccpredict.hgu.mrc.ac.uk/
29. NCCN. (2022, June 8, 2022). Genetic/Familial High-Risk Assessment: Colorectal. NCCN. https://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf
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33. Patel, S. G., May, F. P., Anderson, J. C., Burke, C. A., Dominitz, J. A., Gross, S. A., Jacobson, B. C., Shaukat, A., & Robertson, D. J. (2022). Updates on Age to Start and Stop Colorectal Cancer Screening: Recommendations From the U.S. Multi-Society Task Force on Colorectal Cancer. Gastroenterology, 162(1), 285-299. https://doi.org/https://doi.org/10.1053/j.gastro.2021.10.007 
34. Peltomäki PT, O. G., Vasen HFA. (2010). Lynch syndrome. In C. F. Bosman FT, Hruban RH, Theise ND (Ed.), WHO Classification of Tumours of the Digestive System (4th ed., Vol. 3). IARC Press. 
35. Provenzale, D., Gupta, S., Ahnen, D. J., Bray, T., Cannon, J. A., Cooper, G., David, D. S., Early, D. S., Erwin, D., Ford, J. M., Giardiello, F. M., Grady, W., Halverson, A. L., Hamilton, S. R., Hampel, H., Ismail, M. K., Klapman, J. B., Larson, D. W., Lazenby, A. J., . . . Darlow, S. (2016). Genetic/Familial High-Risk Assessment: Colorectal Version 1.2016, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw, 14(8), 1010-1030. 
36. Rex, D. K., Boland, C. R., Dominitz, J. A., Giardiello, F. M., Johnson, D. A., Kaltenbach, T., Levin, T. R., Lieberman, D., & Robertson, D. J. (2017). Colorectal Cancer Screening: Recommendations for Physicians and Patients from the U.S. Multi-Society Task Force on Colorectal Cancer. Am J Gastroenterol, 112(7), 1016-1030. https://doi.org/10.1038/ajg.2017.174 
37. Robson, M. E., Bradbury, A. R., Arun, B., Domchek, S. M., Ford, J. M., Hampel, H. L., Lipkin, S. M., Syngal, S., Wollins, D. S., & Lindor, N. M. (2015). American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility. J Clin Oncol, 33(31), 3660-3667. https://doi.org/10.1200/jco.2015.63.0996 
38. Robson, M. E., Storm, C. D., Weitzel, J., Wollins, D. S., & Offit, K. (2010). American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol, 28(5), 893-901. https://doi.org/10.1200/jco.2009.27.0660 
39. Rumilla, K., Schowalter, K. V., Lindor, N. M., Thomas, B. C., Mensink, K. A., Gallinger, S., Holter, S., Newcomb, P. A., Potter, J. D., Jenkins, M. A., Hopper, J. L., Long, T. I., Weisenberger, D. J., Haile, R. W., Casey, G., Laird, P. W., Le Marchand, L., & Thibodeau, S. N. (2011). Frequency of deletions of EPCAM (TACSTD1) in MSH2-associated Lynch syndrome cases. J Mol Diagn, 13(1), 93-99. https://doi.org/10.1016/j.jmoldx.2010.11.011 
40. Salvador, M. U., Truelson, M. R. F., Mason, C., Souders, B., LaDuca, H., Dougall, B., Black, M. H., Fulk, K., Profato, J., Gutierrez, S., Jasperson, K., Tippin-Davis, B., Lu, H. M., Gray, P., Shah, S., Chao, E. C., Ghahramani, N., Landsverk, M., Gau, C. L., . . . Pronold, M. (2019). Comprehensive Paired Tumor/Germline Testing for Lynch Syndrome: Bringing Resolution to the Diagnostic Process. J Clin Oncol, 37(8), 647-657. https://doi.org/10.1200/jco.18.00696 
41. Sepulveda, A. R., Hamilton, S. R., Allegra, C. J., Grody, W., Cushman-Vokoun, A. M., Funkhouser, W. K., Kopetz, S. E., Lieu, C., Lindor, N. M., Minsky, B. D., Monzon, F. A., Sargent, D. J., Singh, V. M., Willis, J., Clark, J., Colasacco, C., Rumble, R. B., Temple-Smolkin, R., Ventura, C. B., & Nowak, J. A. (2017). Molecular Biomarkers for the Evaluation of Colorectal Cancer: Guideline From the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology. J Mol Diagn, 19(2), 187-225. https://doi.org/10.1016/j.jmoldx.2016.11.001 
42. Stinton, C., Fraser, H., Al-Khudairy, L., Court, R., Jordan, M., Grammatopoulos, D., & Taylor-Phillips, S. (2021). Testing for lynch syndrome in people with endometrial cancer using immunohistochemistry and microsatellite instability-based testing strategies - A systematic review of test accuracy. Gynecol Oncol, 160(1), 148-160. https://doi.org/10.1016/j.ygyno.2020.10.003 
43. Stjepanovic, N., Moreira, L., Carneiro, F., Balaguer, F., Cervantes, A., Balmaña, J., & Martinelli, E. (2019). Hereditary gastrointestinal cancers: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†. Ann Oncol, 30(10), 1558-1571. https://doi.org/10.1093/annonc/mdz233 
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Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive. 

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