BlueCross and BlueShield of Montana Medical Policy/Codes
Genetic Testing for Inherited Susceptibility to Colon Cancer, Including Microsatellite Instability Testing
Chapter: Genetic Testing
Current Effective Date: October 25, 2013
Original Effective Date: September 01, 2007
Publish Date: October 25, 2013
Revised Dates: July 29, 2011; September 19, 2013

Genetic testing is available for both affected individuals, as well as those at risk, for various types of hereditary colon cancer.  There are currently two well-defined types of hereditary colorectal cancer: familial adenomatous polyposis (FAP) and Lynch syndrome (formerly, hereditary nonpolyposis colorectal cancer or HNPCC).  This policy describes genetic testing for familial adenomatous polyposis (FAP), Lynch syndrome (formerly known as HNPCC), as well as MUTYH (formerly MYH)—associated polyposis (MAP).

Familial adenomatous polyposis and associated variants

FAP typically develops by age 16 years and can be identified by the appearance of hundreds to thousands of characteristic, precancerous colon polyps.  If left untreated, all affected individuals will go on to develop colorectal cancer.  The mean age of colon cancer diagnosis in untreated individuals is 39 years.  FAP accounts for about 1% of colorectal cancer and may also be associated with osteomas of the jaw, skull, and limbs; sebaceous cysts; and pigmented spots on the retina, referred to as congenital hypertrophy of the retinal pigment epithelium (CHRPE).  FAP associated with these collective extraintestinal manifestations is sometimes referred to as Gardner syndrome.  FAP may also be associated with central nervous system (CNS) tumors, referred to as Turcot syndrome.

Germline mutations in the adenomatous polyposis coli (APC) gene, located on chromosome 5, are responsible for FAP and are inherited in an autosomal dominant manner.  Mutations in the APC gene result in altered protein length in about 80% to 85% of cases of FAP.  A specific APC gene mutation (I1307K) has been found in subjects of Ashkenazi Jewish descent that may explain a portion of the familial colorectal cancer occurring in this population.

A subset of FAP patients may have attenuated FAP (AFAP), typically characterized by fewer than 100 cumulative colorectal adenomas occurring later in life than in classical FAP, colorectal cancer occurring at an average age of 50-55 years, but a high lifetime risk of colorectal cancer of about 70% by age 80.  The risk of extra-intestinal cancer is lower compared to classical FAP but still high at an estimated cumulative lifetime risk of 38% compared to the general population (Vogt et al., 2009).  Only 30% or fewer of AFAP patients have APC mutations; some of these patients instead have mutations in the MUTYH (formerly MYH) gene and are then diagnosed with MAP.  MAP occurs with a frequency approximately equal to FAP, with some variability among prevalence estimates for both.  While clinical features of MAP are similar to FAP or AFAP, a strong multigenerational family history of polyposis is absent.  Biallelic MUTYH mutations are associated with a cumulative colorectal cancer risk of about 80% by age 70, whereas monoallelic MUTYH mutation-associated risk of colorectal cancer appears to be relatively minimal, although still under debate (Balmana et al., 2010).  Thus, inheritance for high-risk colorectal cancer predisposition is autosomal recessive in contrast to FAP.  When relatively few (i.e., between 10 and 99) adenomas are present and family history is unavailable, the differential diagnosis may include both MAP and Lynch syndrome; genetic testing in this situation could include APC, MUTYH if APC is negative for mutations, and screening for mutations associated with Lynch syndrome.

It is important to distinguish among classical FAP, AFAP, and MAP (mono- or biallelic) by genetic analysis because recommendations for patient surveillance and cancer prevention vary according to the syndrome (Gala, Chung, 2011).

Genetic testing for APC mutations may be considered for the following types of patients:

  • Family members of patients with FAP and a known APC mutation.  Those without the specific mutation have not inherited the susceptibility gene and can forego intense surveillance (although they retain the same risk as the general population and should continue an appropriate level of surveillance).
  • Patients with a differential diagnosis of AFAP vs. MAP vs. Lynch syndrome.  These patients do not meet the clinical diagnostic criteria for classical FAP and have few adenomatous colonic polyps.
  • Patients with colon cancer with a clinical picture or family history consistent with classical FAP.
  • Lynch syndrome.

Patients with Lynch syndrome have a predisposition to colorectal cancer and other malignancies as a result of an inherited mutation in a DNA mismatch repair (MMR) gene.  Lynch syndrome includes those with an existing cancer and those who have not yet developed cancer.  The term “HNPCC” originated prior to the discovery of explanatory MMR mutations for many of these patients, and now includes some who are negative for MMR mutations and likely have mutations in as-yet unidentified genes.  For purposes of clarity and analysis, the use of Lynch syndrome in place of HNPCC has been recommended in several recent editorials and publications.

Lynch syndrome is estimated to account for 3% to 5% of all colorectal cancer and is also associated with an increased risk of other cancers such as endometrial, ovarian, urinary tract, and biliary tract cancer.  Lynch syndrome is associated with a risk of developing colorectal cancer by age 70 years of approximately 27% to 45% for men, and 22% to 38% for women, after correction for ascertainment bias (Bonadona et al., 2011).  Lynch syndrome patients who have colorectal cancer also have an estimated 16% risk of a second primary within 10 years.

Lynch syndrome is associated with any of a large number of possible mutations in one of several MMR genes, known as MLH1, MSH2, MSH6, PMS2 and rarely MLH3.  Risk of all Lynch syndrome-related cancers is markedly lower for carriers of a mutation in the MSH6 and PMS2 genes, although for most cancers still significantly higher than that of the general population (Gala, Chung, 2011; Bonadona et al., 2011).  Estimated cumulative risks of any associated cancer for a carrier of a mutation in any MMR gene do not begin to increase until after age 30 years.

Lynch syndrome mutations are heterozygous; that is, only one of the two gene alleles contains a mutation.  In rare cases both alleles contain the mutation, i.e., biallelic MMR gene mutations.  This unusual syndrome has been described in multiple families and is to a large extent the result of consanguinity(Dumo et al., 2010)  Children with biallelic MMR mutations may develop extra-colonic cancers in childhood, such as brain tumors, leukemias, or lymphomas.  Those unaffected or surviving early malignancies are at high risk of later colorectal cancer (average age of colorectal cancer diagnosis 16.4 years [Dumo et al., 2010]).  Family history may not suggest Lynch syndrome.  Prior to cancer diagnosis, patients may have multiple adenomatous polyps and thus may have an initial differential diagnosis of AFAP versus MAP versus Lynch syndrome.

About 70% of Lynch syndrome patients have mutations in either MLH1 or MSH2.  Testing for MMR gene mutations is often limited to MLH1 and MSH2 and, if negative, then MSH6 and PMS2 testing.  Large gene sizes and the difficulty of detecting mutations in these genes make direct sequencing a time- and cost-consuming process.  Thus, additional indirect screening methods are needed to determine which patients should proceed to direct sequencing for MMR gene mutations.  Available screening methods are microsatellite instability (MSI) testing or immunohistochemical (IHC) testing.  BRAF testing is an optional screening method that may be used in conjunction with IHC testing for MLH1 to improve efficiency.  A methylation analysis of the MLH1 gene can largely substitute for BRAF testing, or be used in combination to slightly improve efficiency.

Mutations in MMR genes result in a failure of the mismatch repair system to repair errors that occur during the replication of DNA in tumor tissue.  Such errors are characterized by the accumulation of alterations in the length of simple, repetitive microsatellite (2 to 5 base repeats) sequences that are distributed throughout the genome, termed microsatellite instability (MSI) and resulting in a MSI-high tumor phenotype.  MSI testing was standardized subsequent to a 2004 National Cancer Institute (NCI) workshop (Umar et al., 2004).  Methodologic studies have also shown the importance of laser microdissection of the tumor tissue, comparison of tumor and normal cells, and a minimum proportion of tumor in relation to the quality of the test results.  While the sensitivity of MSI testing is high, the specificity is low because approximately 10% of sporadic colorectal cancers are MSI-positive due to somatic hypermethylation of the MLH1 promoter.  Additionally, some tumors positive for MSH6 mutations are associated with the MSI-low phenotype rather than MSI-high; thus MSI-low should not be a criterion against proceeding to MMR mutation testing (Wu et al., 1999; Goel et al, 2010).

Absent or reduced protein expression may be a consequence of an MMR gene mutation.  IHC assays for the expression of MLH1, MSH2, MSH6, and PMS2 can be used to detect loss of expression of these genes and to focus sequencing efforts on a single gene.  It is also possible for IHC assays to show loss of expression, and thus indicate the presence of a mutation, when sequencing is negative for a mutation.  In such cases, mutations may be in unknown regulatory elements and cannot be detected by sequencing of the protein coding regions.  Thus IHC may add additional information.

The BRAF gene is often mutated in colorectal cancer; when a particular BRAF mutation (V600E, a change from valine to glutamic acid at amino acid position 600 in the BRAF protein) is present; to date no MLH1 gene mutations have been reported (Palomaki et al., 2009).  Therefore, patients negative for MLH1 protein expression by IHC, and therefore potentially positive for an MLH1 mutation, could first be screened for a BRAF mutation.  BRAF-positive samples need not be further tested by MLH1 sequencing.  MLH1 gene methylation largely correlates with the presence of BRAF-V600E and in combination with BRAF testing can accurately separate Lynch from sporadic colorectal cancer in IHC MLH1-negative cases (Bouzourene et al., 2010).

Various attempts have been made to identify which patients with colon cancer should undergo testing for MMR mutations, based primarily on family history and related characteristics using criteria such as the Amsterdam II criteria (low sensitivity but high specificity) and the Bethesda guidelines (better sensitivity but poorer specificity).  While family history is an important risk factor and should not be discounted in counseling families, it has poor sensitivity and specificity for identifying Lynch syndrome.  Based on this and other evidence, the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group recommended testing all newly diagnosed patients with colorectal cancer for Lynch syndrome, using a screening strategy based on MSI or IHC (+BRAF) followed by sequencing in screen-positive patients.  This recommendation includes genetic testing for the following types of patients:

  • Family members of Lynch syndrome patients with a known MMR mutation; family members would be tested only for the family mutation; those testing positive would benefit from early and increased surveillance to prevent future colorectal cancer.
  • Patients with a differential diagnosis of Lynch syndrome versus attenuated FAP versus MYH-associated polyposis.
  • Lynch syndrome patients.  Genetic testing of the proband with colorectal cancer likely benefits the proband where Lynch syndrome is identified and appropriate surveillance for associated malignancies can be initiated and maintained and benefits family members by identifying the family mutation.

Recently, novel deletions have been reported to affect the expression of the MSH2 MMR gene in the absence of an MSH2 gene mutation, and thereby cause Lynch syndrome.  In these cases, deletions in EPCAM, the gene for the epithelial cell adhesion molecule, are responsible.  EPCAM testing has been added to many Lynch syndrome profiles and is conducted only when tumor tissue screening results are MSI-high, and/or IHC shows a lack of MSH2 expression, but no MSH2 mutation is found by sequencing.

Separately from patients with EPCAM deletions, rare Lynch syndrome patients have been reported without detectable germline MMR mutations although IHC testing demonstrates a loss of expression of one of the MMR proteins.  In at least some of these cases, research has identified germline "epimutations," i.e., methylation of promoter regions that control the expression of the MMR genes (Hesson et al., 2010; Hitchens, 2010; Niessen et al., 2009).  Such methylation may be isolated or in conjunction with a linked genetic alteration near the affected MMR gene.  The germline epimutations may arise de novo or may be heritable in either Mendelian or non-Mendelian fashion.  This is distinct from some cases of MSI-high sporadic colorectal cancer wherein the tumor tissue may show MLH1 promoter methylation and IHC non-expression, but the same is not true of germline cells.  Clinical testing for Lynch syndrome-related germline epimutations is not routine but may be helpful in exceptional cases.  Epimutations as a cause of Lynch syndrome are described only for informational purposes; no policy statement is made regarding this testing.


Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions.  Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply.  If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.


Adenomatous polyposis coli (APC) gene mutation test for familial adenomatous polyposis (FAP) or attenuated FAP (AFAP) may be considered medically necessary in the following:

  1. Patients with greater than 20 colonic polyps during their lifetime; or
  2. Patients with a *first- or second-degree relative diagnosed with FAP or an APC mutation; or
  3. Patients with a *first- or second-degree relative with known FAP gene mutation.

*Definitions of first- or second-degree relatives, according to the National Comprehensive Cancer Network (NCCN) Guidelines criteria:

  • First-degree relative:  Any relative who is one meiosis away from a particular individual in a family; a relative with whom one-half of an individual’s genes are shared, a 50% genetic link to the patient (i.e., parent, sibling, offspring).
  • Second-degree relative:  Any relative who is two meioses away from a particular individual in a family; a relative with whom one-quarter of an individual's genes are shared, a 25% genetic link to the patient (i.e., grandparent, grandchild, uncle, aunt, nephew, niece, half-sibling).

MUTYH (formerly MYH)—Associated Polyposis (MAP) may be considered medically necessary when either of the following is met:

  1. Patients with personal history of adenomatous polyposis and:
    • Negative result for APC gene mutation test, or
    • Family history consistent with recessive inheritance (family history positive for siblings only); or
  2. Asymptomatic individual who has sibling(s) with known MUTYH-associated polyposis (MAP).

Microsatellite Instability (MSI) and/or the Immunohistochemistry (IHC) analysis of colorectal cancer tissue and/or endometrial cancer tissue may be considered medically necessary as a means of identifying the need to proceed with HNPCC (hereditary nonpolyposis colorectal cancer) mutation analysis in patients who:

  1. Meet the Revised Bethesda Guidelines (** see below); or
  2. Meet the Amsterdam II Clinical Criteria (*** see below); or
  3. Were diagnosed with endometrial cancer before age 50 years.

Lynch Syndrome (HNPCC)—MMR (mismatch repair) genetic testing may be considered medically necessary for patients who:

  1. Meet the Revised Bethesda guidelines (** see below); or
  2. Meet the Amsterdam II Clinical Criteria (*** see below);  or
  3. Were diagnosed with endometrial cancer under age 50; or
  4. Have known MMR mutation in the family (patient should be tested for the known mutation).

NOTE:  When an MMR genetic test is medically necessary, genetic sequencing for MMR gene mutations should be performed with the following priority:  MLH1 and MSH2 first, then MSH6, then PMS6 last if a mutation is not found in the first three genes.

Genetic testing for EPCAM mutations may be considered medically necessary when any one of the following are met:

  1. Patient with colorectal cancer, for the diagnosis of Lynch syndrome, when:
    • Tumor tissue shows lack of MSH2 expression by immunohistochemistry (IHC) and patient is negative for a germline mutation in MSH2; or
    • Tumor tissue shows a high level of microsatellite instability (MSI) and patient is negative for a germline mutation in MSH2, MLH1, PMS2, and MSH6; or
  2. Patient has *first- or second-degree relative with Lynch syndrome with a known EPCAM mutation; or
  3. Patient without colorectal cancer but with a family history meeting the Revised Bethesda Guidelines (**see below), or Amsterdam II Clinical Criteria (*** see below), when no affected family members have been tested for MMR mutations, and when sequencing for MMR mutations is negative.

** Revised Bethesda Guidelines (fulfillment of any criterion meets guidelines):

  • Colorectal carcinoma diagnosed in a patient who is less than 50-years old; or
  • Presence of synchronous (at the same time) or metachronous (at another time, i.e.. a recurrence of) colorectal cancer or other Lynch syndrome-associated tumors, regardless of age; or
  • Colorectal cancer with high microsatellite instability (MSI) histology diagnosed in a patient less than 60-years old; or
  • Colorectal cancer diagnosed in one or more *first-degree relatives with a Lynch syndrome-associated tumor, with one of the cancers being diagnosed at less than 50 years of age; or
  • Colorectal cancer diagnosed in two or more *first-degree or second-degree relatives with Lynch syndrome-associated tumor(s)****, regardless of age. 

*** Amsterdam II Clinical Criteria (all criteria must be fulfilled)

  • Three or more relatives with Lynch syndrome-associated tumor(s)****; and
  • One must be a *first-degree relative of the other two; and
  • Two or more successive generations must be affected; and
  • One or more of the relatives should be diagnosed before the age of 50 years; and
  • Familial adenomatous polyposis (FAP) should be excluded in cases of colorectal carcinoma; and
  • Tumors should be verified by pathologic examination whenever possible.
  • NOTE:  Modifications may apply for:
    • EITHER: very small families, which cannot be further expanded, can be considered to have HNPCC with only two colorectal cancers in first-degree relatives if at least two generations have the cancer and at least one case of colorectal cancer was diagnosed by the age of 55 years;
    • OR: in families with two *first-degree relatives affected by colorectal cancer, the presence of a third relative with an unusual early-onset neoplasm or endometrial cancer is sufficient.

**** LYNCH SYNDROME-ASSOCIATED TUMORS include colorectal, endometrial, gastric, ovarian, pancreas, ureter and renal pelvis, biliary tract, brain (usually glioblastoma as seen in Turcot syndrome), and small intestinal cancers, as well as sebaceous gland adenomas and ketatoacanthomas as seen in Muir-Torre syndrome.

Policy Guidelines

Genetic testing is not widely available and may be performed by commercial reference labs or research labs dedicated to genetic testing in general.


FAP Genetic Testing

The policy for FAP genetic testing is based on a 1998 Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) Assessment, which offered the following conclusions:

  • Genetic testing for familial adenomatous polyposis (FAP) may improve health outcomes by identifying which currently unaffected at-risk family members require intense surveillance or prophylactic colectomy.
  • At-risk subjects are considered to be those with greater than 10 adenomatous polyps; or close relatives of patients with clinically diagnosed FAP or of patients with an identified APC mutation.
  • The optimal testing strategy is to define the specific genetic mutation in an affected family member and then test the unaffected family members to see if they have inherited the same mutation.

The additional policy information on attenuated FAP (AFAP) and on MUTYH-associated polyposis (MAP) diagnostic criteria and genetic testing is based on information from GeneReviews (Burt et al., 2008) and from several publications (Kastrinos, Syngal, 2007; Lefevre et al., 2009; Avezzu et al., 2008; Balaguer et al., 2007) that build on prior, cited research.  In addition, GeneReviews summarizes clinical FAP genotype-phenotype correlations that could be used to determine different patient management strategies.  The authors of the review conclude, however, that there is not yet agreement about using such correlations to direct management choices.

The National Comprehensive Cancer Network (NCCN) recommends APC genetic testing in a proband (index case), if possible, to confirm a diagnosis of FAP and allow for mutation-specific testing in other family members.

Lynch Syndrome Genetic Testing

The policy for Lynch syndrome is based on an evidence report published by the Agency for Healthcare Research and Quality (AHRQ) (Bonis et al.), a supplemental assessment to that report contracted by the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group (Palomaki et al., 2009), and an EGAPP recommendation for genetic testing in colorectal cancer (Group EoGAiPaPEW, 2009).  Based on the AHRQ report and supplemental assessment, the EGAPP recommendation came to the following conclusions regarding genetic testing for MMR mutations in patients already diagnosed with colorectal cancer:

  • Family history, while important information to elicit and consider in each case, has poor sensitivity and specificity as a screening test to determine who should be considered for MMR mutation testing and should not be used as a sole determinant or screening test.
  • MSI [microsatellite instability] and IHC [immunohistochemical] screening tests for MMR mutations have similar sensitivity and specificity.  MSI screening has a sensitivity of about 89% for MLH1 and MSH2 and 77% for MSH6 and a specificity of about 90% for all.  It is likely that, using high-quality MSI testing methods, these parameters can be improved.  IHC screening has a sensitivity for MLH1, MSH2, and MSH6 of about 83% and a specificity of about 90% for all.
  • Optional BRAF testing can be used to reduce the number of patients, who are negative for MLH1 expression by IHC, needing MLH1 gene sequencing, thus improving efficiency without reducing sensitivity for MMR mutations.
  • A chain of indirect evidence can be constructed for the clinical utility of testing all patients with colorectal cancer for MMR mutations.
    1. The chain of indirect evidence from well-designed experimental nonrandomized studies (as noted below) is adequate to demonstrate the clinical utility of testing unaffected (without cancer) first- and second-degree relatives of patients with Lynch syndrome who have a known MMR mutation.
    2. Seven studies examined how counseling affected testing and surveillance choices among unaffected family members of Lynch syndrome patients.  About half of relatives received counseling, and 95% of these chose MMR gene mutation testing.  Among those positive for MMR gene mutations, uptake of colonoscopic surveillance beginning at age 20–25 years was high at 53–100%.
      • One long-term, nonrandomized controlled study and one cohort study of Lynch syndrome family members found significant reductions in colorectal cancer among those who followed recommended colonic surveillance vs. those who did not.
      • Surveillance, prevention for other Lynch syndrome cancers (for detail, refer to last outline bullet).
    3. The chain of evidence from descriptive studies and expert opinion (as noted below) is inadequate (inconclusive) to demonstrate the clinical utility of testing the probands with Lynch syndrome (i.e., cancer index patient).
      • Subtotal colectomy is recommended as an alternative to segmental resection, but has not been shown superior in follow-up studies.
      • Although a small body of evidence suggests that MSI-positive tumors are resistant to 5-fluorouracil and more sensitive to irinotecan than MSI-negative tumors, no alteration in therapy according to MSI status has yet been recommended.
      • Surveillance, prevention for other Lynch syndrome cancers:

i.      While invasive and not actively recommended, women may choose hysterectomy with salpingo-oophorectomy to prevent gynecologic cancer.  In one retrospective study, women who chose this option had no gynecologic cancer over 10 years, whereas about one-third of women who did not have surgery developed endometrial cancer, and 5.5% developed ovarian cancer

ii.     In one study, surveillance endometrial biopsy detected endometrial cancer and potentially precancerous conditions at earlier stages in those with Lynch syndrome, but results were not statistically significant, and a survival benefit has yet to be  shown.  Transvaginal ultrasound (TVUS) is not a highly effective surveillance mechanism for endometrial cancer in patients with Lynch syndrome; however, TVUS in conjunction with endometrial biopsy has been recommended for surveillance.     

iii.    Gastroduodenoscopy for gastric cancer surveillance and urine cytology for urinary tract cancer surveillance are recommended based on expert opinion only, in the absence of adequate supportive evidence.

Based on an indirect chain of evidence with adequate evidence of benefit to unaffected family members found to have Lynch syndrome, the EGAPP working group recommended testing all patients with colorectal cancer for MMR gene mutations.

In addition to DNA mismatch repair (MMR) gene mutation testing, evidence now supports testing for EPCAM deletions in particular cases where all MMR gene mutation testing is negative, but tumor MSH2 IHC indicates lack of expression, and tumor MSI testing shows a high level of instability.  EPCAM is found just upstream, in a transcriptional sense, of MSH2.  Deletions of EPCAM that encompass the last two exons of the EPCAM gene including the polyadenylation signal that normally ends transcription of DNA into messenger RNA result in transcriptional ‘read-through’ and subsequent hypermethylation of the nearby and downstream MSH2 promoter.  This hypermethylation prevents normal MSH2 protein expression and leads to Lynch syndrome in a fashion similar to Lynch cases in which an MSH2 mutation prevents MSH2 gene expression.  Several studies have characterized such EPCAM deletions, established their correlation with the presence of EPCAM-MSH2 fusion messenger RNAs (apparently non-functional) and with the presence of MSH2 promoter hypermethylation, and, most importantly, have shown the co-segregation of these EPCAM mutations with Lynch-like disease in families (Niessen et al., 2009; Kloor et al., 2011; Kuiper et al., 2011; Kovacs et al., 2009; Ligtenberg et al., 2009; Rumilla et al., 2011).  Because studies differ slightly in how patients were selected, prevalence of these EPCAM mutations is difficult to estimate but may be in the range of 20-40% of patients/families who meet Lynch syndrome criteria, do not have a MMR mutation, but have MSI-high tumor tissue.  Kempers et al. reported that carriers of an EPCAM deletion had a 75% (95% confidence interval [CI], 65–85) cumulative risk of colorectal cancer by age 70 years, not significantly different from that of carriers of an MSH2 deletion (77%, 64–90); mean age at diagnosis was 43 years.  However, the cumulative risk of endometrial cancer was low at 12% (95% CI, 0–27) by age 70, compared to carriers of a mutation in MSH2 (51% [95% CI, 33–69], p=0.0006) (Kempers et al., 2011).

Although MMR gene sequencing of all patients is the most sensitive strategy, it is highly inefficient and cost-ineffective and not recommended.  Rather, a screening strategy of MSI or IHC testing (with or without optional BRAF testing) is recommended and retains a relatively high sensitivity.  Some evidence suggests that IHC requires particular training and experience (Overbeek et al., 2008).  Although a particular strategy was not recommended by the EGAPP Working Group, several are potentially effective; efficiency and cost-effectiveness may depend upon local factors.

Previous recommendations have used family history as an initial screen to determine who should proceed further to MMR laboratory testing.  Recent studies have shown that limiting laboratory testing to patients who met even the more sensitive Revised Bethesda criteria (i.e., compared to the Amsterdam II criteria) would miss as much as 28% of Lynch syndrome cases (Hampel et al., 2008; Canard et al., 2011).  Family history is important for counseling families, but based on this and similar evidence, is not recommended as an initial screening tool to make decisions about testing patients who already have colorectal cancer.  However, the Amsterdam II or Revised Bethesda criteria may be used in identifying those without colorectal cancer who might be tested.

Limiting testing for Lynch Syndrome on the basis of age (e.g., test only patients younger than age 50 years) is also not recommended.  For example, Hampel et al. found that among 18 Lynch syndrome patients discovered among 500 unselected colorectal cancer patients, only 8 (44%) patients were diagnosed at age younger than 50 years.  Similarly, Canard et al. reported that restricting screening to patients younger than 50 years would have missed about half of patients eventually found to have Lynch Syndrome.  Another group screened colorectal cancer patients who were younger than age 60 and identified 98 likely (MSI positive, BRAF negative) Lynch syndrome cases; of these, 47% were between ages 50 and 60 (Schofield et al., 2009).  A large study of Lynch syndrome family studies found that the cumulative risk of colorectal cancer in MMR mutation carriers was only 13% (95% CI, 9-19) by age 50, but 35% (95% CI, 25-49%) by age 70 (Bonadona et al., 2011).  For MSH6 mutation carriers, however, colorectal cancer risks do not appear to increase until after age 60.

The estimated risk of stomach cancer in a large study of Lynch syndrome families was 6% (95% CI, 0.2-17%) for carriers of MLH1 mutations and warrants further study to address the utility of gastric surveillance (Bonadona et al., 2011).

As the EGAPP recommendations noted, the evidence to date is limited to clearly support benefit from genetic testing to the index patient with colorectal cancer if found to have Lynch syndrome.  However, professional societies have reviewed the evidence and concluded that genetic testing likely has direct benefits for at least some patients with colorectal cancer and Lynch syndrome on the basis of differing recommendations for post-surgical surveillance, and for those who choose prophylactic surgical treatment instead of surveillance.  

In the absence of preventive surgery, heightened surveillance is recommended.  The NCCN guidelines for colon cancer and for colorectal cancer screening recommend post-surgical colonoscopy at one year and, if normal, again in 2-3 years, then every 3-5 years based on findings.  However, for Lynch syndrome patients, colonoscopy is recommended every 1-2 years throughout life based on the high likelihood of cancer for patients diagnosed with Lynch syndrome prior to a cancer diagnosis, and on the high likelihood of a second primary cancer in those diagnosed with Lynch syndrome based on a first cancer diagnosis (deVos et al., 2002).  If the patient is not a candidate for routine surveillance, subtotal colectomy may be considered (NCCN, 2011).

Early documentation of the natural history of colorectal cancer in highly selected families with a strong history of hereditary colorectal cancer indicated risks of synchronous and metachronous cancers as high as 18% and 24%, respectively, in patients who already had colorectal cancer (Fitzgibbons et al., 1987).  As a result, in 1996, the Cancer Genetic Studies Consortium, a temporary NIH (National Institutes of Health)-appointed body, recommended that if colorectal cancer is diagnosed in patients with an identified mutation or a strong family history, a subtotal colectomy with ileorectal anastomosis (IRA) should be considered in preference to segmental resection (Burke et al.,1997).  Although the average risk of a second primary is now estimated to be somewhat lower overall (see Description) in patients with Lynch syndrome and colorectal cancer, effective prevention measures remain imperative.  One study suggested that subtotal colectomy with IRA markedly reduced the incidence of second surgery for metachronous cancer from 28% to 6% but could not rule out the impact of surveillance (Van Dalen et al., 2003).  A mathematical model comparing total colectomy and IRA to hemicolectomy resulted in increased life expectancies of 2.3, 1, and 0.3 years for ages 27, 47, and 67, respectively; for Duke’s A, life expectancies for the same ages are 3.4, 1.5, and 0.4, respectively (de Vos et al., 2003).  Based on this work, the joint American Society of Clinical Oncology (ASCO) and Society of Surgical Oncology (SSO) review of risk-reducing surgery in hereditary cancers recommends offering both options to the patient with Lynch syndrome and colorectal cancer, especially those who are younger (Guillem et al., 2006).  This ASCO/SSO review also recommends offering Lynch syndrome patients with an index rectal cancer the options of total proctocolectomy with ileal pouch anal anastomosis or anterior proctosigmoidectomy with primary reconstruction.  The rationale for total proctocolectomy is the 17% to 45% rate of metachronous colon cancer in the remaining colon after an index rectal cancer in Lynch syndrome patients.

The ASCO/SSO review recommends offering prophylactic total abdominal hysterectomy to female patients with colorectal cancer who have completed childbearing or to women undergoing abdominal surgery for other conditions, especially when there is a family history of endometrial cancer.  This recommendation is based on the high rate of endometrial cancer in mutation-positive individuals and the lack of efficacy of screening.  A recent study estimated the risk of endometrial cancer in mutation carriers at 34% (95% CI, 17-60%) by age 70, and of ovarian cancer 8% (95% CI, 2-39%) by age 70 (Bonadona et al., 2011).  Risks do not appear to appreciably increase until after age 40.  When surgery is chosen, oophorectomy should also be performed because of the risk of ovarian cancer in Lynch syndrome.  As already noted, in one retrospective study, women who chose this option had no gynecologic cancer over 10 years whereas about one-third of women who did not have surgery developed endometrial cancer, and 5.5% developed ovarian cancer (Schmeler et al., 2006).  In another retrospective cohort study, hysterectomy improved survival among female colon cancer survivors with Lynch syndrome (Obermair et al., 2010).  This study also estimated that for every 100 women diagnosed with Lynch syndrome-associated colorectal cancer, about 23 will be diagnosed with endometrial cancer within 10 years absent a hysterectomy.  Recent data on mutation-specific risks suggests that prophylactic gynecological surgery benefits for carriers of MSH6 mutations may offer less obvious benefits compared to harms as lifetime risk of endometrial cancer is lower than for carriers of MLH1 or MSH2 mutations, and lifetime risk of ovarian cancer is similar to the risk for the general population (Bonadona et al., 2011).  An alternative to prophylactic surgery is surveillance for endometrial cancer using transvaginal ultrasound (TVUS) and endometrial biopsy.  Evidence indicates that such surveillance significantly reduces the risk of interval cancers, but no evidence as yet indicates surveillance reduces mortality due to endometrial cancer (Auranen et al., 2011)  Surveillance in Lynch syndrome populations for ovarian cancer has not yet been demonstrated successful at improving survival (Auranen et al., 2011).  

The European Society for Medical Oncology (ESMO) published clinical practice guidelines for familial colorectal cancer risk in 2010 (Balmana et al., 2010).  These guidelines addressed Lynch Syndrome, familial adenomatous polyposis, and MAP.  No specific recommendations were made regarding how to initially identify Lynch syndrome cases; several methods, including clinical criteria and universal screening of all colorectal cancer cases, were mentioned.  Other ESMO recommendations are consistent with the information in this policy.

NCCN guideline for colorectal cancer screening notes that screening of all colorectal and endometrial cancers for Lynch syndrome mutations has been implemented at some centers and does not recommend for or against this practice.  The guideline does not specifically mention EPCAM deletion testing but does indicate that individuals with loss of MSH2 and/or MSH6 protein expression by IHC, regardless of germline MMR mutation status, should be followed as though they have Lynch syndrome.  These guidelines also address FAP, AFAP, and MAP, consistent with the information in this policy.


Results of testing for the APC mutation in individuals with a family history of FAP, or a known APC mutation in the family, lead to changes in surveillance and prophylactic treatment.  For patients with a positive result, enhanced surveillance and/or prophylactic treatment will reduce the future incidence of colon cancer and improve health outcomes.  Therefore APC testing may be medically necessary for patients with a family history of FAP or a known APC mutation in the family.  A related familial polyposis syndrome, MAP syndrome, is associated with mutations in the MUTYH gene.  Testing for this genetic mutation may be medically necessary when the differential diagnosis includes both FAP and MAP, since distinguishing between the two leads to different management strategies.  In some cases, Lynch syndrome may be part of the same differential diagnosis, depending on presentation.

A substantial portion of patients with colorectal cancer will be found to have Lynch syndrome, which is associated with mutations in the MMR gene.  A positive genetic test for the MMR mutation can lead to enhanced surveillance, changes in recommendations about treatment options, and possible prophylactic treatment for other Lynch syndrome malignancies., Therefore, testing for Lynch syndrome may be medically necessary in patients with newly diagnosed colorectal cancer and in patients at high risk for Lynch syndrome, defined by meeting the clinical criteria such as Amsterdam II or Revised Bethesda.  The EPCAM mutation is less common than MMR mutations as a cause of Lynch syndrome, and should be part of the diagnostic testing for Lynch syndrome in patients who are negative for all MMR mutations but who screen positive for MSI and lack MSH2 IHC evidence of protein expression.


Disclaimer for coding information on Medical Policies           

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.           

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers.  Only the written coverage position in a medical policy should be used for such determinations.           

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.

Rationale for Benefit Administration


ICD-9 Codes

153.0-153.9, 154.0, 211.3, 211.4, 230.3, 230.4, V10.05, V10.06, V26.3

ICD-10 Codes

C18.0-C18.9, C19, D01.0-D01.9, D12.0-D12.9, Z31.5, Z85.00-Z85.038, Z85.040-Z85.048, Z80.0

Procedural Codes: 81201, 81202, 81203, 81292, 81293, 81294, 81295, 81296, 81297, 81298, 81299, 81300, 81301, 81317, 81318, 81319, S3833, S3834
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  3. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC).  Genetic Testing for Inherited Susceptibility to Colorectal Cancer: Part I – Adenomatous Polyposis Coli Gene Mutations.  TEC Assessments 1998; Volume 13, TAB 10.
  4. Wu Y, Berends MJ, Mensink RG et al.  Association of hereditary nonpolyposis colorectal cancer-related tumors displaying low microsatellite instability with MSH6 germline mutations.  Am J Hum Genet 1999; 65(5):1291-8.
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  7. Van Dalen R, Church J, McGannon E et al.  Patterns of surgery in patients belonging to amsterdam-positive families.  Dis Colon Rectum 2003; 46(5):617-20.
  8. de Vos tot Nederveen Cappel WH, Buskens E, van Duijvendijk P et al.  Decision analysis in the surgical treatment of colorectal cancer due to a mismatch repair gene defect.  Gut 2003; 52(12):1752-5.
  9. Umar A, Boland CR, Terdiman JP et al.  Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability.  J Natl Cancer Inst 2004; 96(4):261-8.
  10. Guillem JG, Wood WC, Moley JF et al.  ASCO/SSO review of current role of risk-reducing surgery in common hereditary cancer syndromes.  J Clin Oncol 2006; 24(28):4642-60.
  11. Schmeler KM, Lynch HT, Chen LM et al.  Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch syndrome.  N Engl J Med 2006; 354(3):261-9.
  12. Kastrinos F, Syngal S.  Recently identified colon cancer predispositions: MYH and MSH6 mutations.  Semin Oncol 2007; 34(5):418-24.
  13. Balaguer F, Castellvi-Bel S, Castells A et al.  Identification of MYH mutation carriers in colorectal cancer: a multicenter, case-control, population-based study.  Clin Gastroenterol Hepatol 2007; 5(3):379-87.
  14. Bonis P, Trikalinos T, Chung M.  Hereditary Nonpolyposis Colorectal Cancer: Diagnostic Strategies and Their Implications.  U. S. Agency for Healthcare Research and Quality.  Evidence Report/Technology Assessment No. 150 (Prepared by Tufts-New England Medical Center Evidence-based Practice Center under Contract No. 290-02-0022) 2007; AHRQ Publication No. 07-E008 (May).  Available online at: (accessed 2011 November).
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  17. Overbeek LI, Ligtenberg MJ, Willems RW et al.  Interpretation of immunohistochemistry for mismatch repair proteins is only reliable in a specialized setting.  Am J Surg Pathol 2008; 32(8):1246-51.
  18. Hampel H, Frankel WL, Martin E et al.  Feasibility of screening for Lynch syndrome among patients with colorectal cancer.  J Clin Oncol 2008; 26(35):5783-8.
  19. Lefevre JH, Parc Y, Svrcek M et al.  APC, MYH, and the correlation genotype-phenotype in colorectal polyposis.  Ann Surg Oncol 2009; 16(4):871-7.
  20. Vogt S, Jones N, Christian D et al.  Expanded extracolonic tumor spectrum in MUTYH-associated polyposis.  Gastroenterology 2009; 137(6):1976-85 e1-10.
  21. Niessen RC, Hofstra RM, Westers H et al.  Germline hypermethylation of MLH1 and EPCAM deletions are a frequent cause of Lynch syndrome.  Genes Chromosomes Cancer 2009; 48(8):737-44.
  22. Group EoGAiPaPEW.  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(1):35-41.
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  24. Ligtenberg MJ, Kuiper RP, Chan TL et al.  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(1):112-7.
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  26. Palomaki GE, McClain MR, Melillo S et al.  EGAPP supplementary evidence review: DNA testing strategies aimed at reducing morbidity and mortality from Lynch syndrome.  Genet Med 2009; 11(1):42-65.
  27. Goel A, Nagasaka T, Spiegel J et al.  Low frequency of Lynch syndrome among young patients with non-familial colorectal cancer.  Clin Gastroenterol Hepatol 2010; 8(11):966-71.
  28. Bouzourene H, Hutter P, Losi L et al.  Selection of patients with germline MLH1 mutated Lynch syndrome by determination of MLH1 methylation and BRAF mutation.  Fam Cancer 2010; 9(2):167-72.
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  37. Rumilla K, Schowalter KV, Lindor NM et al.  Frequency of deletions of EPCAM (TACSTD1) in MSH2-associated lynch syndrome cases.  J Mol Diagn 2011; 13(1):93-9.
  38. Kempers MJ, Kuiper RP, Ockeloen CW et al.  Risk of colorectal and endometrial cancers in EPCAM deletion-positive Lynch syndrome: a cohort study.  Lancet Oncol 2011; 12(1):49-55.
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  43. Genetic Screening for Inherited Susceptibility to Colon Cancer Including Microsatellite Instability Testing.  Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2011 November) Medicine 2.04.08.
  44. NCCN, National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology, Colon Cancer, v I.2012.  Available online at: (accessed 2011 November).
 July 2011 Policy description and rationale extensively rewritten; reference list completely revised. Policy statements changed to indicate expanded medical necessity criteria. Intent of other policy statements generally unchanged, although requirement for positive family history no longer required for testing. Added CPT code S3833 to policy
October 2013 Policy formatting and language revised. 
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Genetic Testing for Inherited Susceptibility to Colon Cancer, Including Microsatellite Instability Testing