Changes

The laboratory should be consistent in the analysis, interpretation, and reporting of microarray results. The laboratory should have a record of and be familiar with the microarray coverage, including known cancer-associated genes and regions, benign and/or common population CNVs, and common genetic disorders caused by genomic CNVs and/or LOH.

The laboratory should be consistent in the analysis, interpretation, and reporting of microarray results. The laboratory should have a record of and be familiar with the microarray coverage, including known cancer-associated genes and regions, benign and/or common population CNVs, and common genetic disorders caused by genomic CNVs and/or LOH.

'''Systematic evaluation and interpretation of DNA microarrays'''

'''Systematic evaluation and interpretation of DNA microarrays'''

The laboratory should establish the methods for microarray result analysis and interpretation using the following recommendations.

The laboratory should establish the methods for microarray result analysis and interpretation using the following recommendations.

'''Disease-associated genetic aberrations'''

'''Disease-associated genetic aberrations'''

The laboratory should be familiar with recurrent, clonal aberrations associated with particular diagnoses. In addition, the laboratory should be familiar with specific genes known to be pathogenic or to contribute to the pathogenesis of a particular disorder. The medical literature should be used to stay abreast of current disease-specific genetic aberrations, as well as the diagnostic, prognostic, and therapeutic significance of aberrations.

The laboratory should be familiar with recurrent, clonal aberrations associated with particular diagnoses. In addition, the laboratory should be familiar with specific genes known to be pathogenic or to contribute to the pathogenesis of a particular disorder. The medical literature should be used to stay abreast of current disease-specific genetic aberrations, as well as the diagnostic, prognostic, and therapeutic significance of aberrations.

'''CNV interval size and cancer-associated genes'''

'''CNV interval size and cancer-associated genes'''

The size of a CNV is relevant, as larger CNVs encompassing multiple genes are more likely to have a clinical impact; however, very small CNVs that interrupt or delete an established cancer-associated gene may be clinically significant. A single laboratory-established CNV size cutoff or threshold for determination of inclusion of a CNV in a clinical report should not be used as the sole determinant of a call. The laboratory should establish methods for detection of clinically significant CNVs that fall below laboratory-established thresholds, particularly in regions of known cancer-associated genes.

The size of a CNV is relevant, as larger CNVs encompassing multiple genes are more likely to have a clinical impact; however, very small CNVs that interrupt or delete an established cancer-associated gene may be clinically significant. A single laboratory-established CNV size cutoff or threshold for determination of inclusion of a CNV in a clinical report should not be used as the sole determinant of a call. The laboratory should establish methods for detection of clinically significant CNVs that fall below laboratory-established thresholds, particularly in regions of known cancer-associated genes.

'''Genomic content in CNV interval'''

'''Genomic content in CNV interval'''

The genomic content of the CNV should be carefully examined for genes relevant to disorders in the differential diagnosis, gene-rich sequences, or genes known to have a clinical association. CNVs encompassing known oncogenes or tumor suppressor genes may have significance, although the implications of the CNV for the particular disorder or patient being studied may not be clear based on current literature.

The genomic content of the CNV should be carefully examined for genes relevant to disorders in the differential diagnosis, gene-rich sequences, or genes known to have a clinical association. CNVs encompassing known oncogenes or tumor suppressor genes may have significance, although the implications of the CNV for the particular disorder or patient being studied may not be clear based on current literature.

'''Copy-number-neutral ROHs detected by SNP analysis'''

'''Copy-number-neutral ROHs detected by SNP analysis'''

Thresholds or minimal criteria to identify clinically important ROHs consistent with LOH (LOH or AOH) should be established. ROHs associated with parental consanguinity or uniparental disomy should be distinguished from acquired LOH. Distinction of acquired versus constitutional AOH may be facilitated by detection of the clonal aberration in affected tissue (acquired LOH) and/or detection (or not) of the aberration in unaffected tissue (constitutional LOH). Homozygosity in a region that contains a tumor suppressor gene may be associated with an inherited cancer predisposition syndrome. Constitutional analysis should be recommended as appropriate.

Thresholds or minimal criteria to identify clinically important ROHs consistent with LOH (LOH or AOH) should be established. ROHs associated with parental consanguinity or uniparental disomy should be distinguished from acquired LOH. Distinction of acquired versus constitutional AOH may be facilitated by detection of the clonal aberration in affected tissue (acquired LOH) and/or detection (or not) of the aberration in unaffected tissue (constitutional LOH). Homozygosity in a region that contains a tumor suppressor gene may be associated with an inherited cancer predisposition syndrome. Constitutional analysis should be recommended as appropriate.

'''Comparison of CNV to internal and external databases'''

'''Comparison of CNV to internal and external databases'''

Laboratories should document pathogenic CNVs, CNVs of uncertain significance, benign CNVs, and CNVs thought or determined to be constitutional. The intralaboratory data should be used along with external data as a reference for interpretation of data from new studies.

Laboratories should document pathogenic CNVs, CNVs of uncertain significance, benign CNVs, and CNVs thought or determined to be constitutional. The intralaboratory data should be used along with external data as a reference for interpretation of data from new studies.

'''Categories of clinical significance'''

'''Categories of clinical significance'''

Using the guidelines outlined above for systematic investigation of a CNV for clinical significance, it is recommended that the interpreting laboratory geneticist use the following categories for reporting. Consistent terminology will facilitate unambiguous communication of clinical significance. Taking into account that tumors may be genetically complex, it may not be feasible to provide a detailed interpretation of every CNV and/or AOH region detected. In such cases, a narrative to describe variants and their clinical significance and interpretation should be provided to communicate the desired information. When feasible, the laboratory should provide details of specific CNV and AOH anomalies.

Using the guidelines outlined above for systematic investigation of a CNV for clinical significance, it is recommended that the interpreting laboratory geneticist use the following categories for reporting. Consistent terminology will facilitate unambiguous communication of clinical significance. Taking into account that tumors may be genetically complex, it may not be feasible to provide a detailed interpretation of every CNV and/or AOH region detected. In such cases, a narrative to describe variants and their clinical significance and interpretation should be provided to communicate the desired information. When feasible, the laboratory should provide details of specific CNV and AOH anomalies.

'''Pathogenic'''

'''Pathogenic'''