Hereditary Pancreatic Cancer Panel, Sequencing and Deletion/Duplication

To compare directly to other hereditary cancer panels offered by ARUP Laboratories, see the Hereditary Cancer Panel Comparison table.

  • Recommended test to confirm a hereditary cause of pancreatic cancer in individuals with a personal or family history
  • Testing minors for adult-onset conditions is not recommended. Testing will not be performed on minors without prior approval. For additional information, please contact an ARUP genetic counselor at 800-242-2787.
  • Testing for a known familial sequence variant by sequencing gene of interest. A copy of the family member’s test result documenting the familial gene variant is REQUIRED.
  • To determine if the variant(s) of interest are detectable by this assay, contact an ARUP genetic counselor.

Pathogenic germline variants in multiple genes have been implicated in hereditary pancreatic cancer. Hereditary cancer syndromes are often characterized by early age of cancer onset (typically before 50 years of age) and multiple, multifocal, and/or similar cancers in a single individual or in a closely related family member(s). See Genes Tested table for more details regarding the genes and syndromes included on the Hereditary Pancreatic Cancer Panel. Genes included on this panel are also included on other related tests (see Related Tests section and Hereditary Cancer Genetic Testing – Germline Testing for Inherited Cancer Syndromes).

Genetics

Genes

See Genes Tested table for genes included in the panel.

Etiology

Approximately 10% of pancreatic cancers are associated with a hereditary cause. 

Inheritance

  • Autosomal dominant
  • Some genes are also associated with autosomal recessive childhood cancer predisposition or other syndromes.

Test Interpretation

Contraindications for Ordering

  • Individuals with a suspected diagnosis of Lynch syndrome should consider the Lynch Syndrome Panel, Sequencing and Deletion/Duplication (3001605) due to inclusion of the recurrent MSH2 inversion and an increased detection of single exon deletions/duplications.
  • Should not be ordered to detect somatic variants associated with malignancy because sensitivity for mosaic variants is low with methodology used for germline assays
  • Individuals with hematological malignancy and/or a previous allogeneic bone marrow transplant should not undergo molecular genetic testing on peripheral blood specimen.
    • Testing of cultured fibroblasts is required for accurate interpretation of test results.

Methodology

This test is performed using the following sequence of steps:

  • Selected genomic regions, primarily coding exons and exon-intron boundaries, from the targeted genes are isolated from extracted genomic DNA using a probe-based hybrid capture enrichment workflow.
  • Enriched DNA is sequenced by massively parallel sequencing (MPS; also known as next generation sequencing [NGS]) followed by paired-end read alignment and variant calling using a custom bioinformatics pipeline. The pipeline includes an algorithm for detection of large (single exon-level or larger) deletions and duplications.
  • Sanger sequencing is performed as necessary to fill in regions of low coverage and in certain situations, to confirm variant calls.
  • Large deletion/duplication calls made using MPS are confirmed by an orthogonal exon-level microarray when sample quality and technical conditions allow.
  • Long-range PCR followed by nested Sanger sequencing is performed on the following gene and exons:
    • PMS2 (NM_000535) 11, 12, 13, 14, 15
  • Bidirectional Sanger sequencing is performed on the following gene and exon:
    • MSH2 (NM_000251) 5
    • PMS2 (NM_000535) 7
  • Multiplex ligation-dependent probe amplification (MLPA) is performed on the following gene to call exon-level deletions and duplications:
    • PMS2 (NM_000535)

Sensitivity/Specificity

Clinical Sensitivity

Variable, dependent on phenotype

Analytic Sensitivity/Specificity

Variant Class Analytic Sensitivity (PPA) Estimatea (%)
and 95% Credibility Region (%)
Analytic Specificity (NPA) Estimate (%)

SNVs

>99 (96.9-99.4)

>99.9

Deletions 1-10 bpb

93.8 (84.3-98.2)

>99.9

Insertions 1-10 bpb

94.8 (86.8-98.5)

>99.9

Exon-levelc deletions

97.8 (90.3-99.8) [2 exons or larger]

62.5 (38.3-82.6) [single exon]

>99.9

Exon-levelc duplications

83.3 (56.4-96.4) [3 exons or larger]

>99.9

Exon-level deletions/duplications (MLPA)

>99

>99

aPPA values are derived from larger methods-based MPS and/or Sanger validations. These values do not apply to testing performed by MLPA unless otherwise indicated.

bVariants greater than 10 bp may be detected, but the analytic sensitivity may be reduced.

cIn most cases, a single exon deletion or duplication is less than 450 bp and 3 exons span a genomic region larger than 700 bp.

bp, base pairs; MLPA, multiplex ligation-dependent probe amplification; NPA, negative percent agreement; PPA, positive percent agreement; SNVs, single nucleotide variants

Limitations

  • A negative result does not exclude a heritable form of cancer.
  • Diagnostic errors can occur due to rare sequence variations.
  • Interpretation of this test result may be impacted if this patient has had an allogeneic stem cell transplantation.
  • The following will not be evaluated:
    • Variants outside the coding regions and intron-exon boundaries of targeted genes
    • Regulatory region and deep intronic variants
    • Breakpoints of large deletions/duplications
    • Sequence variants in EPCAM
    • The following exons are not sequenced due to technical limitations of the assay:
      • APC (NM_001354896) 12; (NM_001354898, NM_001354904) 2; (NM_001354900) 11
      • BRCA1 (NM_007300) 13
      • MEN1 (NM_001370251) 8
      • VHL (NM_001354723) 2
  • The following may not be detected:
    • Deletions/duplications/insertions of any size by MPS
    • Large duplications less than 3 exons in size
    • Noncoding transcripts
    • Single exon deletions/duplications may not be detected based on the breakpoints of the rearrangement.
    • Some variants due to technical limitations in the presence of pseudogenes, repetitive, or homologous regions
    • Low-level somatic variants
    • Deletions/duplications in the following exons:
      • APC (NM_001354896) 12; (NM_001354898, NM_001354904) 2; (NM_001354900) 11
      • BRCA1 (NM_007294, NM_007299, NM_007300) 2; (NM_007298) 1
      • CDKN2A (NM_000077, NM_001195132, NM_001363763, NM_058195) 2
      • MEN1 (NM_001370251) 8
      • VHL (NM_001354723) 2

Genes Tested

To compare directly to other hereditary cancer panels offered by ARUP Laboratories, see the Hereditary Cancer Panel Comparison table.

Gene MIM Number Disorder/Associated Cancer(s)/Tumor(s) Inheritance

APC

611731

FAP

AFAP

GAPPS

Colorectal adenomas and cancer, duodenal adenomas and cancer, gastric fundic gland polyps, medulloblastoma, osteomas, pancreatic, thyroid, and others

AD

ATM

607585

Breast, colorectal,a ovarian, pancreatic, prostate

AD

Ataxia-telangiectasia

AR

BRCA1

113705

HBOC syndrome

Breast, fallopian tube, ovarian, pancreatic, peritoneal, prostate

AD

Fanconi anemia, complementation group S

AR

BRCA2

600185

HBOC syndrome

Breast, fallopian tube, melanoma, ovarian, pancreatic, peritoneal, prostate

AD

Fanconi anemia, complementation group D1

AR

CDK4

123829

Cutaneous melanoma, pancreatica

AD

CDKN2A

600160

FAMMM-PC syndrome (also known as melanoma-pancreatic cancer syndrome)

Cutaneous melanoma, pancreatic

AD

EPCAM

(Exon 9 deletion/duplications only)

185535

Lynch syndrome/HNPCC

Brain, colorectal, endometrial, ovarian, pancreatic, prostate, renal pelvis and/or ureter, stomach, and others

AD

MEN1

613733

MEN type 1

Adrenocortical, carcinoid, GEP neuroendocrine tumors, meningioma, parathyroid, pituitary, thyroid

AD

MLH1

120436

Lynch syndrome/HNPCC

Brain, colorectal, endometrial, ovarian, pancreas, prostate, renal pelvis and/or ureter, stomach, and others

AD

CMMRD

AR

MSH2

609309

Lynch syndrome/HNPCC

Brain, colorectal, endometrial, ovarian, pancreas, prostate, renal pelvis and/or ureter, stomach, and others

AD

CMMRD

AR

MSH6

600678

Lynch syndrome/HNPCC

Brain, colorectal, endometrial, ovarian, pancreas, prostate, renal pelvis and/or ureter, stomach, and others

AD

CMMRD

AR

PALB2

610355

Breast, ovarian, pancreas, prostate

AD

Fanconi anemia, complementation group N

AR

PMS2

600259

Lynch syndrome/HNPCC

Brain, colorectal, endometrial, ovarian, pancreas, prostate, renal pelvis and/or ureter, stomach, and others

AD

CMMRD

AR

STK11

602216

 

PJS

Breast, cervix, colorectal, endometrial, lung, ovarian (sex cord with annular tubules), pancreas, Peutz-Jeghers-type hamartomatous polyps, small intestine, stomach, testes

AD

TP53

191170

LFS

Adrenocortical carcinoma, breast, choroid plexus carcinoma, CNS, colorectal, melanoma, osteosarcoma, pancreas, prostate, renal, rhabdomyosarcoma, soft tissue sarcoma, stomach, thyroid, and others

AD

VHL

608537

VHL syndrome

Endolymphatic sac tumors, epididymal and broad ligament cystadenomas, hemangioblastoma, neuroendocrine tumors, pheochromocytoma, renal cell carcinoma, retinal angioma

AD

aAssociation is suggested but not well-established at this time.

AD, autosomal dominant; AFAP, attenuated familial adenomatous polyposis; AR, autosomal recessive; CMMRD, constitutional mismatch repair deficiency; CNS, central nervous system; FAMMM-PC, familial atypical multiple mole melanoma-pancreatic carcinoma; FAP, familial adenomatous polyposis; GAPPS, gastric adenocarcinoma and proximal polyposis of the stomach; GEP, gastro-entero-pancreatic; GIST, gastrointestinal stromal tumor; HBOC, hereditary breast and ovarian cancer; HNPCC, hereditary nonpolyposis colorectal cancer; JPS, juvenile polyposis syndrome; LFS, Li-Fraumeni syndrome; MAP, MUTYH-associated polyposis; MEN, multiple endocrine neoplasia; PJS, Peutz-Jeghers syndrome; VHL, von Hippel-Lindau

References