Invitae Constitutional Mismatch Repair-Deficiency Panel


Test description

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.

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Primary panel (5 genes)


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).

Constitutional mismatch repair-deficiency (CMMR-D)

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:

  • a brain tumor or leukemia that was diagnosed before age 18
  • a second primary cancer
  • café-au-lait macules and/or other signs of NF1 or hypopigmented skin lesions
  • consanguineous parents
  • a family history of Lynch syndrome-associated cancers
  • a sibling with a childhood cancer

Clinical diagnostic criteria for CMMR-D have also been proposed:

Assay and technical information

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, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
EPCAM* NM_002354.2
MLH1* NM_000249.3
MSH2* NM_000251.2
MSH6 NM_000179.2
PMS2 NM_000535.5

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).