This test analyzes the genes associated with constitutional mismatch repair-deficiency (CMMR-D), which is a childhood cancer predisposition syndrome. Individuals who have biallelic pathogenic variants in any one of these genes can develop CMMR-D.
Genetic testing of these genes may confirm a diagnosis and help guide treatment and management decisions. Identification of a disease-causing variant would also guide testing and diagnosis of at-risk relatives. This test is specifically designed for heritable germline mutations and is not appropriate for the detection of somatic mutations in tumor tissue.
EPCAM MLH1 MSH2 MSH6 PMS2
EPCAM MLH1 MSH2 MSH6 PMS2
Constitutional mismatch repair-deficiency (CMMR-D) is a childhood-onset cancer predisposition syndrome that can present with hematological malignancies, cancers of the brain and central nervous system, Lynch syndrome-associated cancers (colon, uterine, small bowel, urinary tract), embryonic tumors, and sarcomas. Using immunohistochemistry to screen tumors and normal tissues for abnormal expression of MMR gene products may lead to an early diagnosis. Some affected individuals may also display some features of neurofibromatosis type 1—most often cafe-au-lait macules.
CMMR-D is highly penetrant, meaning that most affected individuals will manifest features of this condition, but the specific lifetime risk for an individual of developing each type of CMMR-D-related cancer is unknown. Most cancers develop in childhood and adolescence.
CMMR-D is inherited in an autosomal recessive pattern. Carriers of a single pathogenic variant in one of these genes may have Lynch syndrome.
The prevalence of CMMR-D is currently unknown, but it seems to be very rare.
CMMR-D should be considered in individuals with:
Clinical diagnostic criteria for CMMR-D have also been proposed:
Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).
Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.
Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.
|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|
EPCAM: Analysis is limited to deletion/duplication analysis.
MLH1: Deletion/duplication analysis covers the promoter region.
MSH2: Analysis includes the exon 1-7 inversion (Boland mutation).