Test Catalog

Test ID: BCLL    
IGH Somatic Hypermutation Analysis, B-Cell Chronic Lymphocytic Leukemia (B-CLL), Varies

Useful For Suggests clinical disorders or settings where the test may be helpful

Providing prognostic information in patients with newly diagnosed B-cell chronic lymphocytic leukemia


This test is not intended for use in providing prognostic information for patient with other B-cell neoplasms or hematopoietic tumors.

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

During early B-cell development, IGH genes are assembled from multiple polymorphic gene segments that undergo rearrangements and selection, generating variable diversity joining (VDJ) combinations that are unique in both length and sequence for each B cell. In addition, new acquired (somatic) point variations are introduced into the variable (V) regions of mature B cells during the germinal center reaction in lymph nodes, and this process is called somatic hypermutation (SHM). Since chronic lymphocytic leukemia (CLL) originates from the malignant transformation of single lymphoid cells, each daughter cell shares 1 or (sometimes) more unique "clonal" antigen receptor gene rearrangements, which are cell and, therefore, tumor specific (ie, a tumor cell "fingerprint"). Clonal IGHV gene hypermutation status provides important prognostic information for patients with CLL and small lymphocytic lymphoma (SLL). The presence of IGH SHM is defined as greater than 2% difference from the germline VH gene sequence identity (mutated), whereas less than or equal to 2% difference is considered no SHM (unmutated). The status of SHM has clear influence on the median survival of CLL patients. Hypermutation of the IGH variable region is strongly predictive of a good prognosis, while lack of variants predicts a poorer prognosis.

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

An interpretive report will be provided.

Interpretation Provides information to assist in interpretation of the test results

The presence or absence of somatic hypermutation (SHM) in the immunoglobulin heavy chain gene (IGH) variable (V) region DNA will be reported. A variation frequency of greater than 2% will be reported as mutated. Both the percent mutation and the V region allele identified in the rearrangement will be included in the report.


B-cell chronic lymphocytic leukemia (B-CLL) lacking SHM of the IGH V region (unmutated) is associated with a significantly worse prognosis than B-CLL containing SHM of the IGH V region (mutated).

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

This test is useful for patients with chronic lymphocytic leukemia (CLL), or small lymphocytic lymphoma (SLL) with blood or bone marrow involvement. The prognostic value of somatic IGH V (IGHV) region mutation status is applicable only for this subtype of B-cell malignancy.


This test requires a minimum monoclonal CLL B-cell percentage in order to amplify the clonal IGH gene rearrangement. This level has been established at 5% of lymphocytes (eg, as determined by flow cytometric immunophenotyping). A CLL population below 5% will not have a reliable or reproducible clonal gene rearrangement and sequencing by next-generation sequencing to determine somatic mutation status will typically produce no results, or possibly a false-positive finding. Therefore, submitted CLL samples must have a minimum CLL monoclonal B-cell population of 5% of total lymphocytes.


The prognostic significance of somatic hypermutation (SHM) status is only known when a single functional IGH rearrangement is identified (ie, in frame junctional coding region with no predicted premature protein truncation). However, a variety of situations can occur, for which the clinical significance is unknown at this time. These can broadly be grouped into the following:

1. Greater than 1 functional rearrangement is identified, with discordant mutation status

2. Only nonfunctional rearrangements are identified


Rearrangements with mutation status at or near the 2% cutoff should be interpreted with caution for the purposes of prognosis, particularly if the entire IGHV sequence could not be sequenced due to the use of framework region 1 (FR1) V region primers. If such results are identified, an appropriate comment will be provided in the report.

Clinical Reference Recommendations for in-depth reading of a clinical nature

1. Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK: Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood. 1999 Sep 15;94(6)::1848-1854

2. Damle RN, Wasil T, Fais F, et al: Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood. 1999 Sep 15;94(6):1840-1847

3. Langerak AW, Davi F, Ghia P, et al: Immunoglobulin sequence analysis and prognostication in CLL: guidelines from the ERIC review board for reliable interpretation of problematic cases. Leukemia. 2011 Jun;25(6):979-984. doi: 10.1038/leu.2011.49

Special Instructions Library of PDFs including pertinent information and forms related to the test