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Pancreatic Cancer Comprehensive Panel

Diseases Targeted:

Hereditary Pancreatic Cancer

Overview:

The Pancreatic Cancer Comprehensive Panel examines 22 genes associated with an increased risk for hereditary pancreatic cancer. This test includes both well-established pancreatic cancer susceptibility genes, as well as candidate genes with limited evidence of an association with pancreatic cancer.

Who is this test for?

Patients with a personal or family history suggestive of a hereditary pancreatic cancer syndrome. Red flags for hereditary pancreatic cancer could include onset of cancer prior to the age of 50 years, more than one primary cancer in a single person, and multiple affected people within a family. This test is appropriate for patients with both isolated pancreatic cancer, as well as those that may have other clinical findings suggestive of a genetic syndrome. Other cancers that can sometimes co-occur in families with a syndrome that increases the risk for pancreatic cancer could include melanoma and breast, ovarian, colorectal, gastric, or thyroid cancer, among others. After consideration of a patient’s clinical and family history, this testing may be appropriate for some pediatric patients. (If there are specific genes that you do NOT want included, please indicate this on the test requisition form.) This test is designed to detect individuals with a germline pathogenic variant, and is not validated to detect mosaicism below the level of 20%. It should not be ordered on tumor tissue.

What are the potential benefits for my patient?

Patients identified with hereditary pancreatic cancer can benefit from increased surveillance and preventative steps to better manage their risk for cancer. Information obtained from candidate gene testing may potentially be helpful in guiding clinical management in the future. Also, if an inherited susceptibility is found, your patient’s family members can be tested to help define their risk. If a pathogenic variant is identified in your patient, close relatives (children, siblings, parents) could have as high as a 50% risk to also be at increased risk. In some cases, screening should begin in childhood.

Order Options

Sequencing (included)
Del/Dup (included)

 

Genes

APC, ATM, BMPR1A, BRCA1, BRCA2, CDK4, CDKN2A, EPCAM, FANCC, MEN1, MLH1, MSH2, MSH6, NF1, PALB2, PMS2, SMAD4, STK11, TP53, TSC1, TSC2, VHL ( 22 genes )

Coverage:

99% at 50x

Specimen Requirements:

Blood (two 4ml EDTA tubes, lavender top) or Extracted DNA (3ug in EB buffer) or Buccal Swab or Saliva (kits available upon request)

Test Limitations:

Test results and variant interpretation are based on the proper identification of the submitted specimen and use of correct human reference sequences at the queried loci. In very rare instances, errors may result due to mix-up or co-mingling of specimens. Positive results do not imply that there are no other contributions, genetic or otherwise, to the patient's phenotype, and negative results do not rule out a genetic cause for the indication for testing. Result interpretation is based on the collected information and Alamut annotation available at the time of reporting. This assay is not designed or validated for the detection of mosaicism. DNA alterations in regulatory regions or deep intronic regions (greater than 20bp from an exon) will not be detected by this test. There are technical limitations on the ability of DNA sequencing to detect small insertions and deletions. Our laboratory uses a sensitive detection algorithm, however these types of alterations are not detected as reliably as single nucleotide variants. Rarely, due to systematic chemical, computational, or human error, DNA variants may be missed. Although next generation sequencing technologies and our bioinformatics analysis significantly reduce the confounding contribution of pseudogene sequences or other highly-homologous sequences, sometimes these may still interfere with the technical ability of the assay to identify pathogenic variant alleles in both sequencing and deletion/duplication analyses. Deletion/duplication analysis can identify alterations of genomic regions which are a single exon in size. When novel DNA duplications are identified, it is not possible to discern the genomic location or orientation of the duplicated segment, hence the effect of the duplication cannot be predicted. Where deletions are detected, it is not always possible to determine whether the predicted product will remain in-frame or not. Unless otherwise indicated, in regions that have been sequenced by Sanger, deletion/duplication analysis has not been performed.

Patients with Bone Marrow Transplants:
DNA extracted from cultured fibroblasts should be submitted instead of blood/saliva/buccal samples from individuals who have undergone allogeneic bone marrow transplant and from patients with hematologic malignancy.

Gene Specifics:

Gene Notes
MSH2 Inversion of MSH2 exons 1-7 ("Boland" inversion) is assessed for Lynch Syndrome, Colorectal, Endometrial, and Prostate Cancer Panel testing (for both Focus and Comprehensive Panels) as well as Comprehensive Gastric Cancer Panel testing. Unless otherwise specified, this testing is not performed for other cancer panels, but is available upon request.

CPT Codes:

CPT Code 81445, 81479

NOTE: The CPT codes listed on the website are in accordance with Current Procedural Terminology, a publication of the American Medical Association. CPT codes are provided here for the convenience of our clients. Clients who bill for services should make the final decision on which codes to use.

Gene Descriptions:

Gene Reason Reference
APC Heterozygous pathogenic variants in APC are associated with both classic and attenuated familial adenomatous polyposis (FAP), Gardner syndrome, Turcot syndrome, and Hereditary Desmoid disease. PubMed: 20301519; OMIM: 175100
ATM Heterozygous pathogenic variants in ATM are associated with an increased risk for pancreatic and breast cancer. Additionally, biallelic pathogenic variants in ATM have been associated with ataxia-telangiectasia. PubMed: 15928302, 22585167, 20301790, 28418444; OMIM: 607585
BMPR1A Heterozygous pathogenic variants in BMPR1A are associated with Juvenile Polyposis Syndrome (JPS). PubMed: 17303595, 20301642, 9869523; OMIM: 174900
BRCA1 Autosomal dominant pathogenic variants in the BRCA1 gene are the most common cause of hereditary breast and ovarian cancer syndrome (HBOC), which includes approximately a 1-3% risk to develop pancreatic cancer. PubMed: 9497246, 12677558, 17416853, 20301425, 22846731
BRCA2 Autosomal dominant mutations in the BRCA2 gene are implicated in the hereditary breast and ovarian cancer syndrome (HBOC), which includes an increased risk for pancreatic cancer. Additionally, biallelic mutations in BRCA2 gene are associated with autosomal recessive Fanconi anemia Type D1 . PubMed: 12065746, 12677558, 9497246, 17416853, 18042939, 20301425, 22846731, 22187320
CDK4 Heterozygous pathogenic CDK4 variants are associated with an increased risk for melanoma. There is currently limited evidence of an association between CDK4 and risk for pancreatic cancer. PubMed: 17047042, 28283772, 26337759
CDKN2A Heterozygous pathogenic CDKN2A variants are associated with an increased risk for hereditary melanoma and familial atypical multiple mole melanoma-pancreatic carcinoma (FAMMPC) syndrome. PubMed: 28283772, 26337759, 21249757, 19260062; OMIM: 600160
FANCC Biallelic pathogenic variants in FANCC are responsible for approximately 14% of Fanconi Anemia cases. Studies examining pancreatic cancer risk for heterozygous carriers of pathogenic FANCC variants are contradictory, and additional research is needed. PubMed: 20301575, 12750283, 14726700, 26778106; OMIM: 613899, 227645
MSH6 While heterozygous pathogenic variants in MSH6 are associated with Hereditary Non-Polyposis Colorectal Cancer (HNPCC), also known as Lynch Syndrome, biallelic pathogenic variants have been associated with constitutional mismatch repair deficiency syndrome (CMMRD). PubMed: 20301390, 22692065; OMIM: 120436
EPCAM Heterozygous pathogenic variants in the EPCAM gene cause Hereditary Non-Polyposis Colorectal Cancer (HNPCC), also known as Lynch Syndrome, which increases the risk for pancreatic cancer. PubMed: 20301390, 23462293
SMAD4 Heterozygous pathogenic variants in SMAD4 are associated with Juvenile Polyposis Syndrome (JPS). Biallelic pathogenic variants cause Hereditary Hemorrhagic Telangiectasia (HHT). PubMed: 19553198, 20301642
MEN1 Autosomal dominant pathogenic variants in the gene MEN1 cause Multiple endocrine neoplasia type 1 (MEN1), which is associated with an increased risk for both endocrine and non-endocrine tumors, including insulinomas and endocrine pancreatic tumors. PubMed: 20301710; OMIM: 131100
MLH1 While heterozygous pathogenic variants in MLH1 are associated with Hereditary Non-Polyposis Colorectal Cancer (HNPCC), also known as Lynch Syndrome, biallelic pathogenic variants have been associated with constitutional mismatch repair deficiency syndrome (CMMRD). PubMed: 20301390, 22692065; OMIM: 120436
MSH2 While heterozygous pathogenic variants in MSH2 are associated with Hereditary Non-Polyposis Colorectal Cancer (HNPCC), also known as Lynch Syndrome, biallelic pathogenic variants have been associated with constitutional mismatch repair deficiency syndrome (CMMRD). PubMed: 20301390, 22692065; OMIM: 120436
NF1 Autosomal dominant pathogenic variants in NF1 cause Neurofibromatosis Type 1, which is associated with several types of benign tumors and cancer. There is some evidence that patients with Neurofibromatosis Type 1 may be at an increased risk for insulinomas and pancreatic endocrine tumors; however, additional research is needed given the rarity of this finding. PubMed: 27787920, 26413978, 16861979, 17636453, 20301288, 9639526; OMIM: 613113
PMS2 While heterozygous pathogenic variants in PMS2 are associated with Hereditary Non-Polyposis Colorectal Cancer (HNPCC), also known as Lynch Syndrome; biallelic pathogenic variants have been associated with constitutional mismatch repair deficiency syndrome (CMMRD). PubMed: 20301390, 22692065; OMIM: 120436
STK11 Autosomal dominant pathogenic variants in STK11 have been associated with Peutz-Jeghers syndrome (PJS) which is associated with an increased risk for multiple types of cancer, including breast, ovarian, gastric, colorectal, and pancreatic. PubMed: 15121768, 20301443; OMIM: 175200, 260350
TP53 Heterozygous pathogenic variants in the TP53 gene are associated with Li-Fraumeni syndrome, a condition that increases risk for many types of cancer. PubMed: 20301488, 26014290, 2614290; OMIM: 151623, 191170
TSC1 Autosomal dominant pathogenic variants in TSC1 cause Tuberous Sclerosis complex, which is associated with several types of tumors and other clinical conditions, including pancreatic adenomas. PubMed: 20301399; OMIM: 605284
TSC2 Autosomal dominant pathogenic variants in TSC2 cause Tuberous Sclerosis complex, which is associated with several types of tumors and other clinical conditions, including pancreatic adenomas. PubMed: 20301399; OMIM: 191092
VHL Heterozygous pathogenic variants in VHL cause von Hippel-Lindau (VHL) syndrome, which increases the risk for many types of cancer, including pancreatic neuroendocrine tumors, hemangioblastoma, clear cell renal cell carcinoma, and pheochromocytoma. PubMed: 20301636, 27114602, 25834951, 24355456
PALB2 Autosomal dominant pathogenic variants in PALB2 have been associated with an increased risk of some types of cancer, including breast and pancreatic cancer. Biallelic pathogenic variants in PALB2 have been associated with Fanconi anemia of complementation group N (FANCN) . For women, the risk for breast cancer has been estimated to be two to three times greater than the population risk. PubMed: 17200672, 24870022, 17200668, 21285249, 24141787, 25099575; OMIM: 610355
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