Volume 9 Supplement 1
Utilizing microsatellite instability and immunohistochemistry to clinically interpret a novel germline mismatch repair mutation of uncertain significance
© Ducaine et al; licensee BioMed Central Ltd. 2011
Published: 10 March 2011
Lynch syndrome (LS) is responsible for around 2-3% of all colorectal cancers. Germline mutations within one of four mismatch repair (MMR) genes, MLH1, MSH2, MSH6, or PMS2, cause an increased risk in colorectal, endometrial, urinary tract, and other cancers. Tumor screening, by microsatellite instability (MSI) and immunohistochemistry (IHC) analysis, can be utilized prior to mutation analysis in order to streamline the testing process. The following describes the use of MSI and IHC to aid in the clinical interpretation of a novel MMR mutation of uncertain significance and the direct impact on cancer detection.
Materials and methods/results
Family X presented to our cancer genetics clinic with a previously identified MSH2 MMR gene variant of uncertain significance, 1227del12, detected in Sib 1, who was diagnosed with synchronous colon cancers at age 53. This mutation is an in-frame deletion of four amino acids (Gln, Gly, Ile, Asn) in exon 7, which is located in an alpha-helix turn of the protein. Sib 2 had a bladder cancer at 56 years, and Sib 3 had a ureter cancer at 62 years. Sibs 2 and 3 were tested by standard DNA sequencing for the specific VUS. All three Sibs carry the MSH2 1227del12 mutation. This mutation has not been previously reported in the literature; hence clinical interpretation of this VUS was limited. For this reason, coordination of MSI and IHC was pursued for the three Sibs’ tumors. MSI was high for Sibs 2 and 3 and unable to be performed on Sib 1. All three Sibs’ tumors showed concurrent loss of MSH2 and MSH6 by IHC.
This IHC pattern is suspicious of an underlying germline mutation within the MSH2 gene[4, 5]. In addition, both of the tested tumors were MSI-high. Given these results, and a significant family history, Family X was clinically diagnosed with LS, with the MSH2 VUS as the likely cause. Relatives with the VUS were informed to follow LS management recommendations, and those without the VUS should undergo high risk screening[2, 3]. Sib 2 then underwent a colonoscopy one year from a previous unremarkable colonoscopy, and a Stage I, 1.2 cm proximal colon adenocarcinoma with focal mucin production was detected.
This case illustrates the benefit of tumor screening and genetic professional expertise in the clinical interpretation of a MMR VUS as it applies to clinical diagnosis, early detection and management of high risk families.
- Lynch HT, et al.: Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications. Clin Genet 2009, 76: 1–18. 10.1111/j.1399-0004.2009.01230.xPubMed CentralPubMedView ArticleGoogle Scholar
- Lindor NM, et al.: Recommendations for the care of individuals with an inherited predisposition to Lynch syndrome: a systematic review. JAMA 2006,296(12):1507–1517. 10.1001/jama.296.12.1507PubMedView ArticleGoogle Scholar
- National Comprehensive Cancer Network (NCCN) Guidelines 2010. [http://www.nccn.org]
- Hampel H, et al.: Screening for Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med 2005,352(18):1851–60. 10.1056/NEJMoa043146PubMedView ArticleGoogle Scholar
- Shia J, et al.: Immunohistochemistry as first-line screening for detecting colorectal cancer patients at risk for hereditary nonpolyposis colorectal cancer syndrome: a 2-antibody panel may be as predictive as a 4-antibody panel. Am J Surg Pathol 2009,33(11):1639–1645. 10.1097/PAS.0b013e3181b15aa2PubMedView ArticleGoogle Scholar
- Colaris® Technical Specifications, Myriad Genetic Laboratories 2009. [http://www.myriad.com]
This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.