Letter of Medical Necessity
MLH1 Promoter Methylation
A physician or genetic counselor may want to include a letter of medical necessity with a
preauthorization request, claim submission, to facilitate the insurance review process for the
benefit of the patient. Most major insurance companies consider genetic testing medically
necessary to establish a molecular diagnosis of an inheritable disease when specific conditions are
met:
1. The patient displays clinical features, or is at direct risk of inheriting the mutation in question
(pre-symptomatic);
2. The result of the test will directly impact the treatment being delivered to the patient; and
3. After history, physical examination, pedigree analysis, genetic counseling, and completion of
conventional diagnostic studies, a definitive diagnosis remains uncertain.
We encourage health care providers to cover as many of the following points as possible that are
applicable to the patient:

Explanation that the genetic test has been ordered by a physician;

Explanation that the patient has received genetic counseling;

Explanation of the medical necessity for the test requested;

Treatment plan, including specific statements about the anticipated impact of the genetic
test on the patient’s medical management;

Patient's diagnosis and prognosis, including age of onset;

If family history is cited, provide as much family history information as possible (including
specifics about relationship to patient and, for affected family members, cancer site and age
of cancer diagnosis). Alternatively, a detailed three-generation pedigree that contains this
information could be attached and referred to in the body of the letter.
We remind you to read carefully through the entire letter of medical necessity to make sure it
makes sense for your patient.
<On Office Letterhead>
<Date>
<Insurance Company Name>
<Medical Director>, MD
<Address 1>
<Address 2>
<City>, <ST> <ZIP>
Re: <Patient Full Name>
Member ID: <Enter Member ID>
DOB: <MM/DD/YYYY>
Group ID: <Enter Group ID>
Dear Medical Director:
<On Office Letterhead>
<Date>
<Insurance Company Name>
<Medical Director>, MD
<Address 1>
<Address 2>
<City>, <ST> <ZIP>
Re: <Patient Full Name>
Member ID: <Enter Member ID>
DOB: <MM/DD/YYYY>
Group ID: <Enter Group ID>
Dear Medical Director:
I am writing this letter on behalf of my patient, <Patient Name>, to request coverage for the MLH1
Promoter Methylation test. This test will help to distinguish between sporadic and Lynch syndrome
(LS) associated microsatellite unstable (MSI) noncolorectal cancers. The hallmark of LS is a germline
mutation in one of the family of DNA mismatch repair (MMR) protein genes (MLH1, MSH2, MSH6,
PMS2). These proteins function to repair errors in replication of DNA. LS is associated with a high
risk of colon and endometrial cancers, as well as increased risk of urothelial, small bowel,
hepatobiliary, and pancreatic cancer. Furthermore, some sporadic cancers, including 10 to 15
percent of sporadic colon cancers, may exhibit microsatellite instability and loss of MLH1
immunostaining, usually due to acquired hypermethylation of the MLH1 promoter.
The likelihood of a germline (inherited) mutation is very low in those cases where the tumor
demonstrates MLH1 promoter hypermethylation. The likelihood of a germline mutation is higher in
those cases where the tumor lacks MLH1 promoter hypermethylation. Thus, direct assessment of
MLH1 promoter methylation status can be used to help distinguish between a germline mutation
and epigenetic/somatic inactivation of MLH1. This test uses bisulfite conversion followed by realtime PCR.
I am requesting this test for <Patient Name>. This letter documents the medical necessity of this
test to assist in the diagnosis, treatment plan, and prognosis for this patient. Below is additional
information about the patient’s medical history and potential impact of the test results for the
patient’s medical management.
Patient History and Diagnosis:
<Patient Name> is a <Age> -year-old <Gender > with a suspected diagnosis of sporadic or Lynch
syndrome (LS) associated microsatellite unstable (MSI) cancer based on the following symptoms
and clinical findings:
1. <Symptom/Diagnosis #1 with ICD-9 code>
2. <Symptom/Diagnosis #2 with ICD-9 code>
Family History: (if applicable)
<Patient Name> also has a family history, including:
<Family History>
Clinical Impression:
The patient’s symptoms and clinical history, in addition to the family history, are suggestive of
Lynch syndrome. MLH1 Promoter Methylation testing will play an important role in making a
correct diagnosis and in guiding appropriate medical management of the patient. An accurate
diagnosis can assist the patient by:


Indicating the need for germline mismatch repair gene testing
In some individual, indicating that microsatellite instability in a tumor is likely to be sporadic
and therefore spare the expense of germline sequencing.
I recommend that you support this request for coverage of the MLH1 Promoter Methylation testing
for <Patient Name> through ARUP Laboratories test code 2002499, Federal Tax ID# 87-0403206 /
NPI#:1376548271 with the following CPT codes 88381, 81479, G0452. Please feel free to contact
me at <Physician Phone> if you require additional information.
Sincerely,
<Signature>
<Print Name>
References
1. Geiersbach KB, Samowitz WS. Microsatellite instability and colorectal cancer. Arch Pathol
Lab Med. 2011;135:1269–1277
2. Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group.
Recommendations from the EGAPP Working Group: genetic testing strategies in newly
diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality
from Lynch syndrome in relatives. Genet Med. 2009;11:35–41.
3. Herman J G, Umar A, Polyak K, et al. Incidence and functional consequences of hMLH1
promoter hypermethylation in colorectal carcinoma. Proc. Nat. Acad. Sci. 95: 6870-6875,
1998.
4. Bettstetter M, Dechant S, Ruemmele P, et al: Distinction of hereditary nonpolyposis
colorectal cancer and sporadic microsatellite-unstable colorectal cancer through
quantification of MLH1 methylation by real-time PCR. Clin Cancer Res 2007;13:3221-3228
5. Perez-Carbonell, L, Alenda, C, et al. Methylation Analysis of MLH1 Improves the Selection
of Patients for Genetic Testing in Lynch Syndrome, J Mol Diagn. 2010 July; 12(4): 498–504
6. Nakagawa H, Nagasaka T, Cullings HM, Efficient molecular screening of Lynch syndrome by
specific 3' promoter methylation of the MLH1 or BRAF mutation in colorectal cancer with
high-frequency microsatellite instability. Oncol Rep. 2009 Jun;21(6):1577-83
7. Gausachs M, Mur P, Corral J, Pineda M, MLH1 promoter hypermethylation in the analytical
algorithm of Lynch syndrome: a cost-effectiveness study. Eur J Hum Genet. 2012
Jul;20(7):762-8.