This test analyzes CDKN2A and CDK4, genes that are associated with melanoma-pancreatic cancer syndrome (M-PCS), which is also known as familial atypical mole-malignant melanoma syndrome (FAMMM).
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.
CDKN2A and CDK4 can also be ordered as part of a broader panel to test for different types of hereditary cancer, including pancreatic cancer. Depending on the individual’s clinical and family history, one of these broader panels may be appropriate. Any of these broader panels can be ordered at no additional charge.
Most melanoma is sporadic; approximately 5%-12% of cases are hereditary. Up to 40% of hereditary cases are associated with melanoma-pancreatic cancer syndrome (M-PCS), also known as familial atypical mole-malignant melanoma syndrome (FAMMM). The condition is characterized by numerous (>50) atypical nevi that develop at an earlier age than usual. Depending on lifetime sun exposure, affected individuals with atypical nevi have a 28%-67% risk of developing melanoma. Individuals with M-PCS have an increased risk for pancreatic cancer, estimated at approximately 17%.
Pathogenic variants in CDKN2A and CDK4 are associated with M-PCS. CDK4 has so far been documented in only a small number of melanoma families. The dermatologic clinical presentation of CDK4 and CDKN2A pathogenic variants appears to be similar with early-onset cutaneous malignant melanoma with multiple primary melanomas and atypical nevi. Other non-melanoma cancer types have been observed in individuals with CDK4 pathogenic variants (including pancreatic cancer), but too few cases have been reported to establish gene-specific risks.
For individuals with a CDKN2A pathogenic variant, the risk of melanoma is 28%-67%. The lifetime risk of pancreatic cancer is estimated at 17%. There is wide variation in the published cancer-risk estimates associated with CDKN2A, which is noteworthy. The CDK4 gene has limited evidence correlating it with other cancers besides melanoma because the number of reported cases is small.
A pathogenic variant in CDKN2A is found in 35%-40% of families with three or more melanoma cases. To date, more than half of the families with multiple cases of melanoma have no identifiable pathogenic variant.
M-PCS is inherited in an autosomal dominant pattern. The rate of spontaneous de novo CDKN2A and CDK4 mutations is unknown.
Testing for M-PCS by analysis of the CDKN2A and CDK4 genes may be considered in those with:
The American College of Medical Genetics and Genomics has published guidelines to identify candidates for a cancer genetics consultation regarding M-PCS:
For management guidelines please refer to:
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 and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below, depending on the specific gene or test. In addition, the analysis covers select non-coding variants. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.
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|
CDKN2A (p16INK4a): Analysis supports interpretation of the p14 and p16 proteins.