Double Somatic MMR Mutations


What is it and how common is it?

Tumor screening for Lynch syndrome via microsatellite instability (MSI) and/or immunohistochemistry (IHC) staining for absence of mismatch repair (MMR) proteins is recommended in individuals with colorectal and endometrial cancer.1 Those with MSI-high tumors and/or abnormal IHC without MLH1 promoter methylation or the BRAF V600E mutation are at risk of having a germline MMR mutation, and genetic testing for Lynch syndrome is recommended. If a germline MMR mutation is identified, and a diagnosis of Lynch syndrome is made and appropriate surveillance recommendations are made for the patient, and cascade testing can begin for at-risk relatives. However, a subset of patients with MMR deficiency will not have a germline mutation in an MMR gene, leaving their MMR deficiency (dMMR) unexplained.2

Previous studies have shown that 2.5%-3.9% of CRC is unexplained (i.e. those with dMMR without MLH1 methylation or a germline MMR mutation).3-5 Until recently, those patients were thought to have LS caused by an undetected germline MMR mutation. In 2013, the term “Lynch-like syndrome” (LLS) was coined to describe this indeterminate group of patients. The Spanish EPICOLON Consortium assessed 1,705 unselected CRC patients for family history of CRC and found that the incidence of CRC was lowest in sporadic CRC families (0.48), highest in LS families (6.04), and moderately elevated in LLS families (2.12)5. It was suggested that the LLS group was likely heterogeneous of those with sporadic CRC and those with undetected LS, given the intermediate risk for CRC.6 However, it is now appreciated that many patients with LLS actually have double somatic (DS) MMR mutations in their tumor.

In 2013, one study showed that 16.7% of patients with unexplained dMMR CRC had DS MMR gene mutations, with an additional 27.8% of patients having one MMR mutation identified (they did not assess LOH in this study).7 This study also identified one patient (5.5%) with somatic mosaicism.7 In 2014, three additional studies were performed which determined that 52%-69% of unexplained MMR deficient CRC was caused by DS MMR mutations (either two pathogenic sequence mutations or one pathogenic sequence mutation and loss of heterozygosity).8-10 Other identified causes included previously undetected germline MMR mutations and false tumor screening.8-10 Other studies have shown that patients with DS MMR mutations can still have hereditary CRC caused by MUTYH-associated polyposis and others.11,12

When is somatic testing indicated?

Tumor sequencing may be helpful for individuals with tumor testing showing dMMR and no germline mutation is detected.13

  • CRC/EC patients with MSI-H tumors and normal IHC and BRAF wild-type or absence of MLH1 promoter methylation, and negative germline MMR testing.
  • CRC patients with absent MLH1/PMS2 on IHC and BRAF wild-type or absence of MLH1 promoter methylation, and negative germline MMR testing.
  • EC patients with absent MLH1/PMS2 on IHC and absence of MLH1 promote methylation, and negative germline MMR testing.
  • CRC/EC patients with absent MSH2/MSH6 on IHC, and negative germline MMR testing.
  • CRC/EC patients with absent MSH6 on IHC, and negative germline MMR testing.
    **If applicable, repeat IHC testing on pre-treatment rectal tumors
  • CRC/EC patients with absent PMS2 on IHC, and negative germline MMR testing.

How to manage?

If your patient is found to have DS mutations explaining their dMMR tumor OR if the testing does not help clarify the result, the National Comprehensive Cancer Network recommends that these patients and their close relatives be managed based on their family history and NOT as if they have Lynch syndrome. Genetic consultation should be considered for interpretation of complex results.13


  1. Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group. (2009). 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. Genetics in Medicine: Official Journal of the American College of Medical Genetics, 11(1), 35–41.
  2. Rodríguez–Soler, M., Pérez–Carbonell, L., Guarinos, C., Zapater, P., Castillejo, A., Barberá, V. M., … Jover, R. (2013). Risk of Cancer in Cases of Suspected Lynch Syndrome Without Germline Mutation. Gastroenterology, 144(5), 926–932.e1.
  3. Hampel H, Frankel WL, Martin E, et al. Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med 2005;352:1851-60.
  4. Hampel H, Frankel WL, Martin E, et al. Feasibility of screening for Lynch syndrome among patients with colorectal cancer. J Clin Oncol 2008;26:5783-8.
  5. Rodriguez-Soler M, Perez-Carbonell L, Guarinos C, et al. Risk of cancer in cases of suspected lynch syndrome without germline mutation. Gastroenterology 2013;144:926-932 e1; quiz e13-4.
  6. Boland CR. The mystery of mismatch repair deficiency: lynch or lynch-like? Gastroenterology 2013;144:868-70.
  7. Sourrouille, I., Coulet, F., Lefevre, J. H., Colas, C., Eyries, M., Svrcek, M., … Soubrier, F. (2013). Somatic mosaicism and double somatic hits can lead to MSI colorectal tumors. Familial Cancer, 12(1), 27–33.
  8. Mensenkamp, A. R., Vogelaar, I. P., van Zelst-Stams, W. A. G., Goossens, M., Ouchene, H., Hendriks-Cornelissen, S. J. B., … Ligtenberg, M. J. L. (2014). Somatic mutations in MLH1 and MSH2 are a frequent cause of mismatch-repair deficiency in Lynch syndrome-like tumors. Gastroenterology, 146(3), 643–646.e8.
  9. Haraldsdottir, S., Hampel, H., Tomsic, J., Frankel, W. L., Pearlman, R., de la Chapelle, A., & Pritchard, C. C. (2014). Colon and Endometrial Cancers With Mismatch Repair Deficiency Can Arise From Somatic, Rather Than Germline, Mutations. Gastroenterology, 147(6), 1308–1316.e1.
  10. Geurts-Giele, W. R. R., Leenen, C. H. M., Dubbink, H. J., Meijssen, I. C., Post, E., Sleddens, H. F. B. M., … Dinjens, W. N. M. (2014). Somatic aberrations of mismatch repair genes as a cause of microsatellite-unstable cancers. The Journal of Pathology, 234(4), 548–559.
  11. Morak M, Heidenreich B, Keller G, et al. Biallelic MUTYH mutations can mimic Lynch syndrome. Eur J Hum Genet 2014;22:1334-7.
  12. Pearlman R, Frankel WL, Swanson B, et al. Prevalence and Spectrum of Germline Cancer Susceptibility Gene Mutations Among Patients With Early-Onset Colorectal Cancer. JAMA Oncol 2017;3:464-471.
  13. National Cancer Care Network. Referenced from the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal V.3.2017 National Comprehensive Cancer Network. Accessed April 29, 2018.