FeedbackMassively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray/Sequencing/Multiplex Ligation-dependent Probe Amplification
Polymerase Chain Reaction/Sequencing
Indication for testing:
- Recommended test if there is a known familial sequence variant previously identified in a family member.
- A copy of the family member’s test result documenting the familial variant is required.
See Related Tests
Pathogenic variants in multiple genes have been implicated in hereditary gastrointestinal (GI) cancer. Hereditary cancer predisposition is often characterized by early age of onset (typically before age 50) and multiple, multifocal, and/or similar cancers in a single individual or in a closely related family member. Pathogenic variants in the genes analyzed by this panel cause variable phenotypes and cancer risks, including non-GI cancers. Lynch syndrome, the most common hereditary predisposition to colon cancer, is caused by pathogenic variants in the MLH1, MSH2, MSH6, PMS2, and EPCAM genes.
Disease Overview
Associated Disorder
Lynch Syndrome
Individuals with Lynch syndrome are at increased risk for colorectal, endometrial, stomach, ovarian, and other cancers.
Etiology
At least 2-4% of colorectal cancers are associated with a hereditary cause.
Prevalence
- 1/440 individuals from the general population are estimated to have Lynch syndrome.
- Prevalence of pathogenic variants in the additional genes on this panel is largely unknown.
Inheritance
- All genes tested on the Hereditary GI Cancer Panel are autosomal dominant with the exception of:
- SDHD: autosomal dominant with paternal parent-of-origin effect
- MUTYH: autosomal recessive but may also have autosomal dominant risks that are not well defined
- MSH3 and NTHL1: autosomal recessive
- Some genes are associated with autosomal recessive childhood cancer predisposition or other syndromes.
Test Description
See Genes Tested table for genes included in the panel.
Clinical Sensitivity
- Variable, dependent on phenotype/condition
- Proportion of Lynch syndrome attributed to pathogenic variants in specific mismatch repair (MMR) gene:
Testing Strategy
Contraindications for Ordering
- Should not be ordered to detect somatic variants associated with malignancy as sensitivity for mosaic variants is low with methodology used for germline assays.
- Individuals with hematological malignancy and/or a previous allogenic 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.
- When a relative has a previously identified pathogenic variant, see Familial Mutation, Targeted Sequencing (2001961).
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 individual 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 genes
- Regulatory region variants and deep intronic variants
- Breakpoints of large deletions/duplications
- Deletions/duplications in AXIN2 and MSH3
- Sequence variants in EPCAM
- Noncoding transcripts
- The following exons are not sequenced due to technical limitations of the assay:
- CHEK2 (NM_001349956) 4; (NM_001005735) 3; (NM_007194) 10,12,13,14,15
- SDHC (NM_001035511) 5
- SDHD (NM_001276506) 4
- The following may not be detected:
- Deletions/duplications/insertions of any size by massively parallel sequencing
- Deletions/duplications less than 1kb in the targeted genes by array
- Some variants due to technical limitations in the presence of pseudogenes, repetitive, or homologous regions
- Low-level somatic variants
- Single exon deletions/duplications in the following exons:
- APC (NM_001127511) 1
- BMPR1A (NM_004329) 9
- CDH1 (NM_004360) 1
- CHEK2 (NM_001005735) 3; (NM_007194) 11, 12, 14, 15
- MSH2 (NM_000251) 1; (NM_001258281) 2
- MSH6 (NM_000179) 10
- MUTYH (NM_001128425) 1
- NTHL1 (NM_002528) 3, 4, 5, 6
- POLD1 (NM_002691) 6, 18, 25
- PTEN (NM_000314) 8, 9; (NM_001304717) 1
- SDHD (NM_001276506) 4
- TP53 (NM_001126113) 10; (NM_001126114) 10
Analytical Sensitivity
- For Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) of PMS2: 99%
- For massively parallel sequencing:
| Variant Class | Analytical Sensitivity (PPA) Estimatea (%) | Analytical Sensitivity (PPA) 95% Credibility Regiona (%) |
|---|---|---|
|
SNVs |
99.2 |
96.9-99.4 |
|
Deletions 1-10 bp |
93.8 |
84.3-98.2 |
|
Deletions 11-44 bp |
100 |
87.8-100 |
|
Insertions 1-10 bp |
94.8 |
86.8-98.5 |
|
Insertions 11-23 bp |
100 |
62.1-100 |
|
aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived. bp, base pairs; PPA, positive percent agreement; SNVs, single nucleotide variants |
||
Genes Tested
| Gene | MIM Number | Disorder/Associated Cancer(s)/Tumor(s) | Inheritance |
|---|---|---|---|
|
APC |
611731 |
FAP AFAP GAPPS Associated cancer(s)/tumor(s): colorectal adenomas and cancer, duodenal adenomas and cancer, fundic gland polyps, osteomas, thyroid, pancreas, and others |
AD |
|
AXIN2 |
604025 |
ODCRCS Associated cancer(s): polyposis, colorectala |
AD |
|
BMPR1A |
601299 |
JPS Associated cancer(s)/tumor(s): juvenile polyps, colorectal, stomach, small intestine, pancreas |
AD |
|
CDH1 |
192090 |
HDGC Associated cancer(s)/tumor(s): diffuse gastric, lobular breast |
AD |
|
CHEK2 |
604373 |
Associated cancer(s)/tumor(s): breast, prostate, colorectal, thyroida |
AD |
| EPCAM | 185535 |
Lynch syndrome/HNPCC Associated cancer(s)/tumor(s): colorectal, endometrial, stomach, pancreas, ovarian,a breast,a and others |
AD |
|
MLH1 |
120436 |
Lynch syndrome/HNPCC Associated cancer(s)/tumor(s): colorectal, endometrial, stomach, ovarian, panceas, breast,a and others |
AD |
|
CMMRD |
AR |
||
|
MSH2 |
609309 |
Lynch syndrome/HNPCC Associated cancer(s)/tumor(s): colorectal, endometrial, stomach, ovarian, pancreas, breast,a and others |
AD |
|
CMMRD |
AR |
||
|
MSH3 |
600887 |
Associated cancer(s)/tumor(s): polyposis, colorectala |
AR |
|
MSH6 |
600678 |
Lynch syndrome/HNPCC Associated cancer(s)/tumor(s): colorectal, endometrial, stomach, ovarian, pancreas, breast,a and others |
AD |
|
CMMRD |
AR |
||
|
MUTYH |
604933 |
Associated cancer(s)/tumor(s): breast,a colorectala |
AD |
|
MAP Associated cancer(s)/tumor(s): colorectal adenomas and cancer, duodenal adenomas and cancer |
AR |
||
|
NTHL1 |
602656 |
Associated cancer(s)/tumor(s): polyposis, colorectala |
AR |
|
PMS2 |
600259 |
Lynch syndrome/HNPCC Associated cancer(s)/tumor(s): colorectal, endometrial, stomach, ovarian,a breast,a and others |
AD |
|
CMMRD |
AR |
||
|
POLD1 |
174761 |
PPAP Associated cancer(s)/tumor(s): polyposis, colorectala |
AD |
|
POLE |
174762 |
PPAP Associated cancer(s)/tumor(s): polyposis, colorectala |
AD |
|
PTEN |
601728 |
Cowden syndrome/PTEN hamartoma tumor syndrome Associated cancer(s)/tumor(s): breast, endometrial, thyroid, colorectal, renal cell carcinoma |
AD |
|
SDHB |
185470 |
Associated cancer(s)/tumor(s): paraganglioma, pheochromocytoma, GIST, pulmonary chondroma, renal clear cell carcinoma |
AD |
|
SDHC |
602413 |
Associated cancer(s)/tumor(s): paraganglioma, pheochromocytoma, GIST, pulmonary chondroma, renal clear cell carcinoma |
AD |
|
SDHD |
602690 |
Associated cancer(s)/tumor(s): paraganglioma, pheochromocytoma, GIST, pulmonary chondroma, renal clear cell carcinoma |
ADb |
|
SMAD4 |
600993 |
JPS, HHT syndrome Associated cancer(s)/tumor(s): juvenile polyps, colorectal, stomach, small intestine, pancreas |
AD |
|
STK11 |
602216 |
PJS Associated cancer(s)/tumor(s): Peutz-Jeghers-type hamartomatous polyps, breast, colorectal, stomach, small intestine, pancreas, ovarian, testes, lung |
AD |
|
TP53 |
191170 |
LFS Associated cancer(s)/tumor(s): soft tissue sarcoma, osteosarcoma, CNS tumor, breast, colorectal, pancreas,a adrenocortical carcinoma, choroid plexus carcinoma, rhabdomyosarcoma |
AD |
|
aAssociation is suggested but not well-established at this time bPaternal parent-of-origin effect AD, autosomal dominant; AFAP, attenuated FAP; AR, autosomal recessive; 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; MAP, MUTYH-associated polyposis; ODCRCS, oligodontia-colorectal cancer syndrome; PJS, Peutz-Jeghers syndrome; PPAP, polymerase proofreading-associated polyposis |
|||
References
-
26615784
Smith MJ, Urquhart JE, Harkness EF, et al. The contribution of whole gene deletions and large rearrangements to the mutation spectrum in inherited tumor predisposing syndromes. Hum Mutat. 2016;37(3):250-256.
PubMed -
9354786
Miyaki M, Konishi M, Tanaka K, et al. Germline mutation of MSH6 as the cause of hereditary nonpolyposis colorectal cancer. Nat Genet. 1997;17(3):271-272.
PubMed -
11709755
Berends MJW, Wu Y, Sijmons RH, et al. Molecular and clinical characteristics of MSH6 variants: an analysis of 25 index carriers of a germline variant. Am J Hum Genet. 2002;70(1):26-37.
PubMed -
12637487
Peltomäki P. Role of DNA mismatch repair defects in the pathogenesis of human cancer. J Clin Oncol. 2003;21(6):1174-1179.
PubMed -
18602922
Senter L, Clendenning M, Sotamaa K, et al. The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations. Gastroenterology. 2008;135(2):419-428.
PubMed -
21309036
Kuiper RP, Vissers LE, Venkatachalam R, et al. Recurrence and variability of germline EPCAM deletions in Lynch syndrome. Hum Mutat. 2011;32(4):407-414.
PubMed
17003396
Chen S, Wang W, Lee S, et al. Prediction of germline mutations and cancer risk in the Lynch syndrome, JAMA. 2006;296(12):1479-1487.
GeneReviews - DICER1-Related Disorders
Doros L, Schultz KA, Stewart DR, et al. DICER1-related disorders. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews, University of Washington; 1993-2020. [Last update: Apr 2020; Accessed: Jun 2020]
24310308
Hegde M, Ferber M, Mao R, et al. ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis). Genet Med. 2014;16(1):101-116.
GeneReviews - APC-Associated Polyposis Conditions
Jasperson KW, Patel SG, Ahnen DJ. APC-associated polyposis conditions. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews, University of Washington; 1993-2020. [Last Update: Feb 2017; Accessed: Feb 2020]
GeneReviews - Lynch Syndrome
Kohlmann W, Gruber SB. Lynch syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews, University of Washington; 1993-2021. [Last revision: Apr 2018; Accessed: Feb 2020]
GeneReviews - Juvenile Polyposis Syndrome
Larsen Haidle J, Howe JR. Juvenile polyposis syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews, University of Washington; 1993-2020. [Last update: Mar 2017; Accessed: Oct 2020]
NCCN - genetic/familial high-risk assessment: breast, ovarian, and pancreatic v 2.2021
National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology, genetic/familial high-risk assessment: breast, ovarian, and pancreatic. Version 2.2021. [Last updated: Nov 2020; Accessed: Feb 2021]
NCCN - Genetic/familial high-risk assessment: colorectal v1.2020
National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology, genetic/familial high-risk assessment: colorectal, Version 1.2020. [Updated: Jul 2020; Accessed: Feb 2021]
Indication for testing: