Hereditary Gastric Cancer Panel, Sequencing and Deletion/Duplication

Last Literature Review: December 2022 Last Update:

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

  • Recommended test to confirm a hereditary cause of gastric cancer in individuals with a personal or family history of gastric cancer
  • Testing minors for adult-onset conditions is not recommended; testing will not be performed in minors without prior approval. For additional information, please contact an ARUP genetic counselor at 800-242-2787 ext. 2141.

If a familial sequence variant has been previously identified, targeted sequencing for that variant may be appropriate; refer to the Laboratory Test Directory for additional information.

Pathogenic germline variants in multiple genes have been implicated in hereditary gastric cancer. Hereditary gastric cancer syndromes are often characterized by an early age of disease onset (typically before age 50) and multiple, multifocal, and/or similar cancers in a single individual or one or more closely related family members.

Genetics

Genes

Refer to the Genes Tested table for genes included in the panel.

Etiology

Approximately 5-10% of gastric cancers are associated with a hereditary cause.

Inheritance

  • Typically autosomal dominant (AD)
  • Some genes are also associated with autosomal recessive (AR) childhood cancer predisposition or other syndromes.

Test Interpretation

Contraindications for Ordering

  • For individuals with a suspected diagnosis of Lynch syndrome, consider testing specific to Lynch syndrome as some relevant variants are not included on this panel. Refer to Lynch Syndrome - Hereditary Nonpolyposis Colorectal Cancer (HNPCC) for more information.
  • This test should not be ordered to detect somatic variants associated with malignancy because sensitivity for mosaic variants is low with the methodology used for germline assays.
  • Individuals with hematological malignancy and/or a previous allogeneic bone marrow transplant should not undergo molecular genetic testing on a peripheral blood specimen.
    • Testing cultured fibroblasts is required for the 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 the 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 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 polymerase chain reaction (PCR) testing 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 genes and exons:
    • MSH2 (NM_000251) 5
    • PMS2 (NM_000535) 7
  • Multiplex ligation-dependent probe amplification (MLPA) testing is performed on the following genes to call exon-level deletions and duplications:
    • PMS2 (NM_000535)

Sensitivity/Specificity

Clinical Sensitivity

Variable; dependent on phenotype

Analytic Sensitivity

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; NPA, negative percent agreement; PPA, positive percent agreement; SNVs, single nucleotide variants

Limitations

  • A negative result does not exclude a heritable form of gastric cancer or another cancer.
  • Diagnostic errors can occur due to rare sequence variations.
  • The 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 the targeted gene(s)
    • Regulatory region and deep intronic variants
    • Breakpoints of large deletions/duplications
    • Sequence variants in EPCAM
    • The following exons are not sequenced due to the technical limitations of the assay:
      • APC (NM_001354896) 12
      • APC (NM_001354898, NM_001354904) 2
      • APC (NM_001354900) 11
  • 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.
    • Low-level somatic variants
    • Certain other variants due to technical limitations in the presence of pseudogenes and/or repetitive/homologous regions
    • Deletions/duplications in the following exons:
      • APC (NM_001354896) 12
      • APC (NM_001354898, NM_001354904) 2
      • APC (NM_001354900) 11
      • BMPR1A (NM_004329) 12-13
      • CDH1 (NM_001317185) 10
      • CTNNA1 (NM_001290307) 19
      • CTNNA1 (NM_001324002, NM_001324004) 13
      • CTNNA1 (NM_001324003) 15
      • CTNNA1 (NM_001324005) 16

Genes Tested

To compare directly to other hereditary cancer panels offered by ARUP Laboratories, refer to the ARUP 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

BMPR1A

601299

JPS

Colorectal, juvenile polyps, small intestine, stomach

AD

CDH1

192090

HDGC

Diffuse gastric, lobular breast

AD

CTNNA1

116805

Breast,a stomach

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

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

PMS2

600259

Lynch syndrome/HNPCC

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

AD

CMMRD

AR

SMAD4

600993

JPS, HHT syndrome

Colorectal, juvenile polyps, small intestine, and stomach

AD

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

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

AFAP, attenuated familial adenomatous polyposis; CMMRD, constitutional mismatch repair deficiency; CNS, central nervous system; FAP, familial adenomatous polyposis; GAPPS, gastric adenocarcinoma and proximal polyposis of the stomach; HDGC, hereditary diffuse gastric cancer; HHT, hereditary hemorrhagic telangiectasia; HNPCC, hereditary nonpolyposis colorectal cancer; JPS, juvenile polyposis syndrome; LFS, Li-Fraumeni syndrome; PJS, Peutz-Jeghers syndrome