Diagnostic Guidelines and Tools






NCCN Guidelines dramatically increased the guidelines for genetic testing of Lynch syndrome in 2014.  These changes include:

  1. The accepted use of diagnostic tools providing a quick resource to determine whether it is appropriate to prescribe genetic testing for patients who meet a five percent or greater risk threshold for Lynch syndrome have been approved by NCCN.  These include: 
  •          PREMM 1,2,6  (A very quick, 2 minute family history questionaire prediction tool to determine the clinical probability of an individual
  •          carrying a mutation of the basic Lynch cancers of MLH1, MSH2 and MSH6)
  •          MMR Pro - This assessment device developed by Johns Hopkins researchers allows medical health professionals and families to
  •          make decisions about cancer prevention screenings.  Requires download.
  •          Both tools calculates the risk of an indvidual carrying a gene defect and alleviates time necessary to assess family history and is stated
  •          to more accurately identify at risk individuals.  Download page and tool information.

2. A recommendation for panel testing for the five Lynch syndrome genes instead of sequential testing; and;

3. It acknowledged individuals with cancer may directly proceed to genetic testing without having to undergo a complicated and time intensive tissue screening algorithm.



"If you don't ask the right questions, you do not get the right answers. A question asked in the right way often points to its own answer. Asking questions is the A-B-C of diagnosis. Only the inquiring mind solves problems.

-Edward Hodnett (1841-1920)


Some insurance companies still insist upon the patient meeting the older standards of criteria.  It is important to ask the right questions. Most patients are not familiar with the organs of the body or medical terms determining where in the specific organ the cancer occurred.  However, they may recall some terminology, such as, "She had a whipple." or "I think it was between the kidneys and the bladder where it happened."  So, it is important to ask about age and the location of the tumors, trying to decipher where it could have occurred.  Most patients will stop the process of diagnosis if they are required to present their family's medical records.      


Amsterdam Criteria I for HNPCC

The following must be met in order to make a diagnosis of Lynch syndrome:


  • Three affected relatives with verified colorectal cancer
  • One is a first-degree relative of the other two
  • Two successive generations affected
  • One of the relatives with colorectal cancer diagnosed under age fifty
  • Familial Adenamomatus Polyposis (FAP) should be ruled out.



Amsterdam Criteria II for HNPCC

The following must be met in order to make a diagnosis of Lynch syndrome:


  • Three affected relatives with an HNPCC-associated cancer
  • One is a first-degree relative of the other two
  • Two successive generations affected
  • One of the relatives with HNPCC-associated cancer diagnosed under age fifty
  • Familial Adenamomatus Polyposis (FAP) should be ruled out.


Approximately 50% of those meeting the Amsterdam II criteria will have Lynch syndrome.


Assess family history and determine whether or not to refer to a genetic counselor or perform the test.  In some areas, it is taking up to ten months to obtain the services of a genetic counselor, however, some insurance companies will not pay for the genetic test unless genetic counseling services are provided.  Be sure and check with the insurance company to determine their policy.

Before taking the test, be sure and provide informed consent to the patient.  

Testing can be provided through most commercial laboratories.  Make certain the laboratory is able to provide a comprehensive test for each of the genes.  Some do not.  Finally, make sure the lab is CLIA approved and positive tests are run with a second blind test to confirm the results.Be sure and ask the current delay times in providing results.  Some labs are taking up to six to twelve weeks for results to be returned.


                                                                             MOLECULAR TESTING OF TUMORS


The second prong in determining whether or not the patient meets the criteria for diagnostic testing is molecular testing of all colorectal testing of tumors to determine if characteristics of Lynch syndrome exists.  This is commonly referred to by the genetics community as "universal testing."

LSI encourages all colorectal and endometrial cancer tumors be tested for characteristics of Lynch syndrome.  This does not provide a large number of diagnoses annually, however, may identify families which do not meet the family history criteria. This is important as only approximately 50% meet Amsterdam guideline criteria.  

Considering approximately 149,00 cases of colorectal cancer occur annually and 3% may be a result of Lynch syndrome, the maximum of only 4,470 persons tested as a result of colorectal cancer each year hardly puts a dent into the need to diagnose the approximate 700,000 persons in the U.S. alone, believed to be at risk for Lynch syndrome. The likely number of the effect of universal testing resulting in genetic testing is approximately fifty percent or 2,270 persons per year, which would result in approximately 11,350 diagnosed annually if four other family members would consent to genetic testing, as well.

Asking each patient their family history of cancer and aggressively molecularly testing each tumor will significantly reduce the above number of individuals yet to be diagnosed.  The answer and resolution of protecting families with hereditary cancers rests with our physicians to either test our families or refer those who meet the criteria for testing to genetic counselors.

Below is the Bethesda criteria to determine if this testing is necessary as a precursor test for genetic sequencing.  Some insurance companies may require it, so be certain to contact the insurance companies first for their guidelines and obtain approval for genetic testing prior to providing the test.  The input of a genetic counselor is beneficial when performing molecular testing.



Revised Bethesda Guidelines - testing of tumors for microsatellite instability (MSI)

Preliminary MSI testing of tumors should occur in the following situations:

  • Colorectal cancer diagnosed in individuals under the age of 50
  • Presence of synchronous, metachronous colorectal, or other HNPCC-associated tumors, regardless of age
  • Colorectal cancer with the MSI-H histology diagnosed in a patient <60 years of age
  • Colorectal cancer diagnosed in a patient with one or more first-degree relatives with an HNPCC-related tumor, one cancer being diagnosed
  • Colorectal cancer diagnosed in two or more first-degree or second-degree relatives with HNPCC-related tumors, regardless of age


† MSI-H = high microsatellite instability in tumors refers to changes in two or more of the five NCI-recommended panels of microsatellite markers. MSI-L = low microsatellite instability in tumors refers to changes in only one of the five NCI-recommended panels of microsatellite markers.

Hereditary Nonpolyposis Colorectal Cancer (HNPCC)-related tumors include colorectal, endometrial, stomach, ovarian, pancreas, bladder, ureter and renal pelvis, biliary tract, brain (usually glioblastoma as seen in Turcot Syndrome), prostate, sebaceous gland adenomas and keratoacanthomas in Muir-Torre syndrome, and carcinoma of the small bowel.

Breast cancer has been identified as an integral component of LS based upon mismatch repair germline mutation factors in breast cancer tissues from family members who are not only at high risk, but, moreover, who had Lynch syndrome cancers, such as involving the colorectum. Breast cancer is exceedingly common in the population and, therein, its occurence in Lynch syndrome families could be due to chance, but importantly, a subset will likely be integrally related to a germline mismatch repair Lynch syndrome mutation is some LS families. Therefore, it would be prudent to mount a screening and management program for Lynch syndrome in those families where breast cancer is believed to be an integral lesion.


Diagnostic Codes For Lynch Syndrome (Codes Are In The Process Of Change)


NCCN Guidelines Have Been Revised 2014 for Lynch Syndrome HNPCC Cancers  Sign Up and Log In

Revised European Guidelines June 2013

EGAPP Recommendations for Preliminary Screening And Genetic Testing

American Society of Breast Surgeon Guidelines

American Society of Clinical Oncologists Guidelines

ACMG Guidelines 9/17/2013

Society of Gynecological Oncologists Statement on Prophylactic Surgery

AMA Activity For Medical Professionals To Identify High Risk Individuals

National Society of Genetic Counselors



Reviewed 5/18/2014