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Invitae Multi-Cancer Panel
Test description
The Invitae Multi-Cancer Panel analyzes 84 genes associated with hereditary cancers across major organ systems, including:
- breast and gynecologic (breast, ovarian, uterine)
- gastrointestinal (colorectal, gastric, pancreatic)
- endocrine (thyroid, paraganglioma/pheochromocytoma, parathyroid, pituitary)
- genitourinary (renal/urinary tract, prostate)
- skin (melanoma, basal cell carcinoma)
- brain/nervous system
- sarcoma
- hematologic (myelodysplastic syndrome/leukemia)
The Invitae Multi-Cancer Panel is designed to maximize diagnostic yield for individuals with a personal or family history of mixed cancers affecting multiple organ systems.
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.
Genes tested
AIP ALK APC ATM AXIN2 BAP1 BARD1 BLM BMPR1A BRCA1 BRCA2 BRIP1 CASR CDC73 CDH1 CDK4 CDKN1B CDKN1C CDKN2A CEBPA CHEK2 CTNNA1 DICER1 DIS3L2 EGFR EPCAM FH FLCN GATA2 GPC3 GREM1 HOXB13 HRAS KIT MAX MEN1 MET MITF MLH1 MSH2 MSH3 MSH6 MUTYH NBN NF1 NF2 NTHL1 PALB2 PDGFRA PHOX2B PMS2 POLD1 POLE POT1 PRKAR1A PTCH1 PTEN RAD50 RAD51C RAD51D RB1 RECQL4 RET RUNX1 SDHA SDHAF2 SDHB SDHC SDHD SMAD4 SMARCA4 SMARCB1 SMARCE1 STK11 SUFU TERC TERT TMEM127 TP53 TSC1 TSC2 VHL WRN WT1
Order test
Primary panel (84 genes)
Customized gene selection (0 included, 0 excluded)
AIP ALK APC ATM AXIN2 BAP1 BARD1 BLM BMPR1A BRCA1 BRCA2 BRIP1 CASR CDC73 CDH1 CDK4 CDKN1B CDKN1C CDKN2A CEBPA CHEK2 CTNNA1 DICER1 DIS3L2 EGFR EPCAM FH FLCN GATA2 GPC3 GREM1 HOXB13 HRAS KIT MAX MEN1 MET MITF MLH1 MSH2 MSH3 MSH6 MUTYH NBN NF1 NF2 NTHL1 PALB2 PDGFRA PHOX2B PMS2 POLD1 POLE POT1 PRKAR1A PTCH1 PTEN RAD50 RAD51C RAD51D RB1 RECQL4 RET RUNX1 SDHA SDHAF2 SDHB SDHC SDHD SMAD4 SMARCA4 SMARCB1 SMARCE1 STK11 SUFU TERC TERT TMEM127 TP53 TSC1 TSC2 VHL WRN WT1
Clinical information
Disorders tested
- ataxia-telangiectasia (A-T)
- Bloom syndrome
- Carney complex
- constitutional mismatch repair deficiency (CMMR-D)
- Costello syndrome
- Cowden and Cowden-like syndrome
- DICER1 syndrome
- dyskeratosis congenita
- familial acute myeloid leukemia (AML) syndrome
- familial adenomatous polyposis (FAP)
- familial gastrointestinal stromal tumors (GIST)
- familial isolated pituitary adenoma (FIPA)
- familial neuroblastoma
- familial platelet disorder with propensity to myeloid malignancy (FPD/AML)
- Fanconi anemia
- GATA2 deficiency
- Gorlin syndrome (nevoid basal cell carcinoma)
- hereditary breast and ovarian cancer syndrome (HBOC)
- hereditary diffuse gastric cancer (HGDC)
- hereditary papillary renal cell carcinoma
- hereditary paraganglioma-pheochromocytoma syndrome (PGL/PCC)
- juvenile polyposis syndrome (JPS)
- Li-Fraumeni syndrome (LFS)
- Lynch syndrome – also known as hereditary non-polyposis colorectal cancer (HNPCC)
- melanoma-pancreatic cancer syndrome (M-PCS)
- multiple endocrine neoplasia type 1 (MEN1)
- multiple endocrine neoplasia type 2 (MEN2)
- MUTYH-associated polyposis (MAP)
- neurofibromatosis type 1 (NF1)
- neurofibromatosis type 2 (NF2)
- Nijmegen breakage syndrome (NBS)
- oligodontia-colorectal cancer syndrome
- Perlman syndrome
- Peutz-Jeghers syndrome (PJS)
- retinoblastoma
- rhabdoid tumor predisposition syndrome (RTPS)
- Simpson-Golabi-Behmel syndrome (SGBS)
- tuberous sclerosis complex (TSC)
- von Hippel-Lindau syndrome (VHL)
- Werner syndrome
- Wilms tumor-related conditions
Clinical description
The Invitae Multi-Cancer Panel analyzes 84 genes associated with hereditary cancers across several major organ systems. Individuals with a pathogenic variant in one of the genes on this panel have an increased risk of developing cancer, many of which may be difficult both to detect and to treat. Identifying those at elevated risk may guide implementation of additional screening, surveillance and interventions. These efforts may result in risk-reduction and early diagnosis, increasing the chances of successful treatment and survival.
Breast cancer
The average woman’s lifetime risk of developing breast cancer is ~12%. Although there are a number of other genes associated with hereditary breast cancer, hereditary breast and ovarian cancer syndrome (HBOC) due to pathogenic variants in the BRCA1 and BRCA2 genes accounts for most cases in individuals with a strong family history or early onset diagnosis.
Ovarian
The general population risk for ovarian cancer is ~1.3%. Lynch syndrome and hereditary breast and ovarian cancer syndrome (HBOC) are the most common causes of ovarian cancer. In addition, there are other genes on this panel associated with hereditary predisposition to ovarian cancer.
Uterine
The general population risk for uterine cancer is ~2.7%. Lynch syndrome is the most common inherited cause of uterine cancer, although there are a number of other hereditary cancer genes on this panel associated with this cancer type.
Colorectal
Colorectal cancer (CRC) is the third-most-common cancer diagnosis in the United States. Hereditary colorectal cancer syndromes are generally divided into two types: Lynch syndrome and polyposis syndromes. Lynch syndrome, also called hereditary non-polyposis colon cancer (HNPCC), is caused by pathogenic variants in EPCAM, MLH1, MSH2, MSH6 and PMS2 and is the most common inherited cause of colorectal cancer. Polyposis syndromes are characterized by the development of numerous precancerous polyps, which may become malignant. This panel includes genes associated with both Lynch syndrome and polyposis.
Gastric
Gastric cancer occurs in ~1 in 93 individuals in the general population. Gastric adenocarcinomas account for 90%–95% of gastric cancers and are further histologically divided into intestinal type and diffuse type. One cause of hereditary gastric cancer is a pathogenic variant in CDH1, which causes hereditary diffuse gastric cancer syndrome. However, there are a number of other genes in which pathogenic variants increase the risk of gastric tumors. Gastrointestinal stromal tumors (GISTs) are characterized as sarcomas and are rare tumors of the GI tract that account for 1%–3% of all gastric cancers. This panel includes genes that increase risk for each of these types of gastric tumors.
Pancreatic
There are two main types of pancreatic cancer: cancer of the exonic pancreas (pancreatic adenocarcinoma), which accounts for 95% of pancreatic tumors, and pancreatic neuroendocrine tumors. Hereditary pancreatic cancer can be caused by BRCA2 and CDKN2A, as well as by several other genes. This panel includes genes that are most commonly associated with an increased risk for both types of hereditary pancreatic cancer.
Renal/urinary tract
The general population risk of developing kidney cancer is ~1.6%. The lifetime risk of developing bladder cancer is 1%–3.8%, with approximately 75,000 new cases diagnosed in the United States each year. Most cases are sporadic and isolated, but approximately 5% of urinary tract cancers are hereditary. Unlike sporadic cases, hereditary cancers of the kidneys and urinary tract are often characterized by earlier disease onset and multifocal or bilateral tumors. Hereditary urinary tract cancers may also be syndromic and associated with other non-urinary features.
Prostate
Prostate cancer is the fifth-most-common malignancy in the world. A man’s lifetime risk for developing this type of cancer is ~1 in 7 (15%). While most cases of prostate cancer are sporadic and not inherited, approximately 5%–10% of cases are hereditary. This panel includes genes that increase risk for prostate cancer.
Melanoma
Most cases of melanoma are isolated and sporadic. While the number of individuals who have an inherited risk of melanoma is unknown, it is thought to be low. An estimated 8% of individuals with melanoma also have a first-degree relative with melanoma and approximately 1%–2% of people with melanoma have two or more affected close relatives. This panel includes genes associated with a predisposition to melanoma.
Thyroid
Thyroid cancer occurs in ~13 per 100,000 individuals in the general population annually. The most common type of thyroid cancer, accounting for over 90% of all cases, is non-medullary thyroid cancer (NMTC). Approximately 3%–10% of NMTC cases have a familial component. Medullary thyroid carcinoma (MTC) is a relatively uncommon type of thyroid malignancy and is more strongly associated with hereditary cancer syndromes.The familial form of MTC accounts for 20%–25% of cases and is usually a component of multiple endocrine neoplasia type 2 (MEN2), including subtypes MEN2A and MEN2B, or presents as familial MTC (FMTC) syndrome. This panel includes genes associated with a predisposition to hereditary thyroid cancer.
Paraganglioma (PGL) and pheochromocytoma (PCC)
PGL are rare, adult-onset neuroendocrine tumors that may or may not be malignant. PGL can develop throughout the body, from the middle ear and skull base (called head and neck PGL, or HNP) to the adrenal glands (called pheochromocytomas (PCC)). Most cases are sporadic, but approximately one-third are familial and due to an identifiable pathogenic variant in a disease-causing gene. Familial PGL-PCC can be non-syndromic; however, it can also be a feature of an underlying condition such as neurofibromatosis type 1, von Hippel-Lindau syndrome or multiple endocrine neoplasia type 2. This panel includes genes associated with hereditary PGL-PCC.
Brain and nervous system (including central nervous system (CNS) and peripheral nervous system (PNS)
Pituitary adenoma (PA) is one of the most common types of intracranial tumors. Approximately 2% of all PA cases are attributable to FIPA (familial isolated pituitary adenoma) and the AIP gene accounts for ~20% of all FIPA cases. The general population risk for developing a CNS tumor is 0.55%–0.69%. PNS tumors are rare in adults and children; CNS tumors are the most common cancers among children ages 0–19. Approximately 5% of CNS tumors are hereditary and due to a pathogenic variant; the remainder are isolated and occur sporadically. Unlike sporadic cases, both hereditary CNS and PNS tumors may be syndromic and associated with extra-CNS features. This panel includes genes associated with hereditary predisposition to CNS and PNS tumors as well as a common cause of FIPA.
Sarcoma
A sarcoma is a rare type of cancer that develops from a variety of connective tissues including bone, soft tissue, fat, muscle, nerves, fibrous tissues, blood vessels and deep skin tissues. Sarcomas most often develop in the limbs, but they can be found in any part of the body. Most cases of sarcoma are sporadic and not inherited, but several known genetic conditions are associated with an increased risk of sarcoma. Inherited pathogenic variants in certain genes, such as those included on this panel, account for some cases of hereditary sarcoma. Individuals with pathogenic variants in these genes have an increased risk of developing sarcomas and, in some cases, other cancers as well.
Myelodysplastic syndrome (MDS)/leukemia
MDS and acute myeloid leukemia (AML) generally occur in the elderly population and the incidence increases with age. Cases of early onset MDS/AML in children or young adults may be associated with underlying genetic predisposition syndromes. Hereditary MDS or AML may present as part of a particular genetic syndrome that also has additional prominent clinical features. Non-syndromic familial MDS/AML is characterized by a strong family history of MDS or AML without other apparent phenotypic features. Familial occurrences of MDS/AML appear to be rare, but they may be underdiagnosed. This panel includes genes that may increase risk for MDS and leukemia.
Lifetime risks
Individuals with a pathogenic variant identified by the Invitae Multi-Cancer Panel have an increased risk of malignancy compared to the average person, but not everyone with such a variant will actually develop cancer. Further, the same variant may manifest with different symptoms, even among family members. Because we cannot predict which cancers may develop, additional medical management strategies focused on cancer prevention and early detection may be beneficial.
For gene-associated cancer risks:
- Download the Common Hereditary Cancer poster
- Visit the Hereditary Cancer Overview page to view test descriptions for the individual panel pages on other cancer types
Inheritance
The majority of genes on this panel have autosomal dominant inheritance for hereditary cancer predisposition. Several of these genes also have autosomal recessive inheritance, or result in clinically distinct autosomal recessive conditions. For detailed, gene-specific information, please see the individual gene pages.
Considerations for testing
This panel may be considered for individuals with:
- a personal or family history presenting with multiple cancer types that could fit the features of more than one hereditary cancer syndrome
- a clinical history indicative of a hereditary cancer syndrome but a limited pedigree due to small family size or adoption
There are also some common general features suggestive of a family with a hereditary cancer syndrome. These include:
- cancer diagnosed at an unusually young age
- different types of cancer that have occurred independently in the same person
- cancer that has developed in both organs of a set of paired organs (e.g., both kidneys, both breasts)
- several close blood relatives that have the same type of cancer
- unusual cases of a specific cancer type (e.g., male breast cancer)
References
- Cancer Research UK, cancerresearchuk.org. Accessed September 2019.
- National Cancer Institute, Cancer.gov, Accessed September 2019.
- American Society of Clinical Oncology, Cancer. Net Accessed September 2019.
- Desmond, A, et al. Clinical Actionability of Multigene Panel Testing for Hereditary Breast and Ovarian Cancer Risk Assessment. JAMA Oncol. 2015; :None. PMID: 26270727
- Hall, MJ, et al. Gene panel testing for inherited cancer risk. J Natl Compr Canc Netw. 2014; 12(9):1339-46. PMID: 25190699
- LaDuca, H, et al. Utilization of multigene panels in hereditary cancer predisposition testing: analysis of more than 2,000 patients. Genet. Med. 2014; 16(11):830-7. PMID: 24763289
- Kurian, AW, et al. Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment. J. Clin. Oncol. 2014; 32(19):2001-9. PMID: 24733792
- Malkin, D, et al. Predisposition to pediatric and hematologic cancers: a moving target. Am Soc Clin Oncol Educ Book. 2014; :e44-55. PMID: 24857136
- Robson, ME, et al. American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility. J. Clin. Oncol. 2015; 33(31):3660-7. PMID: 26324357
- Garber, JE, Offit, K. Hereditary cancer predisposition syndromes. J. Clin. Oncol. 2005; 23(2):276-92. doi: 10.1200/JCO.2005.10.042. PMID: 15637391
- Hampel, H, et al. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet. Med. 2015; 17(1):70-87. doi: 10.1038/gim.2014.147. PMID: 25394175
Assay
Assay and technical information
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. In addition, the analysis covers the select non-coding variants specifically defined in the table below. 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 |
|---|---|---|---|
| AIP | NM_003977.3 | ||
| ALK | NM_004304.4 | ||
| APC* | NM_000038.5 | ||
| ATM* | NM_000051.3 | ||
| AXIN2 | NM_004655.3 | ||
| BAP1 | NM_004656.3 | ||
| BARD1 | NM_000465.3 | ||
| BLM | NM_000057.3 | ||
| BMPR1A* | NM_004329.2 | ||
| BRCA1* | NM_007294.3 | ||
| BRCA2* | NM_000059.3 | ||
| BRIP1 | NM_032043.2 | ||
| CASR | NM_000388.3 | ||
| CDC73 | NM_024529.4 | ||
| CDH1 | NM_004360.3 | ||
| CDK4 | NM_000075.3 | ||
| CDKN1B | NM_004064.4 | ||
| CDKN1C | NM_000076.2 | ||
| CDKN2A* | NM_000077.4; NM_058195.3 | ||
| CEBPA | NM_004364.4 | ||
| CHEK2 | NM_007194.3 | ||
| CTNNA1 | NM_001903.3 | ||
| DICER1 | NM_177438.2 | ||
| DIS3L2 | NM_152383.4 | ||
| EGFR | NM_005228.3 | ||
| EPCAM* | NM_002354.2 | ||
| FH* | NM_000143.3 | ||
| FLCN | NM_144997.5 | ||
| GATA2 | NM_032638.4 | ||
| GPC3 | NM_004484.3 | ||
| GREM1* | NM_013372.6 | ||
| HOXB13 | NM_006361.5 | ||
| HRAS | NM_005343.2 | ||
| KIT | NM_000222.2 | ||
| MAX | NM_002382.4 | ||
| MEN1 | NM_130799.2 | ||
| MET | NM_001127500.1 | ||
| MITF* | NM_000248.3 | ||
| MLH1* | NM_000249.3 | ||
| MSH2* | NM_000251.2 | ||
| MSH3 | NM_002439.4 | ||
| MSH6 | NM_000179.2 | ||
| MUTYH | NM_001128425.1 | ||
| NBN | NM_002485.4 | ||
| NF1 | NM_000267.3 | ||
| NF2 | NM_000268.3 | ||
| NTHL1 | NM_002528.6 | ||
| PALB2 | NM_024675.3 | ||
| PDGFRA | NM_006206.4 | ||
| PHOX2B* | NM_003924.3 | ||
| PMS2 | NM_000535.5 | ||
| POLD1* | NM_002691.3 | ||
| POLE | NM_006231.3 | ||
| POT1 | NM_015450.2 | ||
| PRKAR1A | NM_002734.4 | ||
| PTCH1 | NM_000264.3 | ||
| PTEN | NM_000314.4 | ||
| RAD50 | NM_005732.3 | ||
| RAD51C | NM_058216.2 | ||
| RAD51D | NM_002878.3 | ||
| RB1 | NM_000321.2 | ||
| RECQL4 | NM_004260.3 | ||
| RET | NM_020975.4 | ||
| RUNX1 | NM_001754.4 | ||
| SDHA* | NM_004168.3 | ||
| SDHAF2 | NM_017841.2 | ||
| SDHB | NM_003000.2 | ||
| SDHC | NM_003001.3 | ||
| SDHD | NM_003002.3 | ||
| SMAD4 | NM_005359.5 | ||
| SMARCA4 | NM_001128849.1 | ||
| SMARCB1 | NM_003073.3 | ||
| SMARCE1 | NM_003079.4 | ||
| STK11 | NM_000455.4 | ||
| SUFU | NM_016169.3 | ||
| TERC | NR_001566.1 | ||
| TERT | NM_198253.2 | ||
| TMEM127 | NM_017849.3 | ||
| TP53* | NM_000546.5 | ||
| TSC1 | NM_000368.4 | ||
| TSC2 | NM_000548.3 | ||
| VHL | NM_000551.3 | ||
| WRN* | NM_000553.4 | ||
| WT1 | NM_024426.4 |
APC: The 1B promoter region is covered by both sequencing and deletion/duplication analysis. The 1A promoter region is covered by deletion/duplication analysis.
ATM: Sequencing analysis for exons 24 includes only cds +/- 10 bp.
BMPR1A: Deletion/duplication analysis covers the promoter region.
BRCA1: Sequence analysis includes +/- 20 base pairs of adjacent intronic sequence.
BRCA2: Sequence analysis includes +/- 20 base pairs of adjacent intronic sequence.
CDKN2A (p14ARF): CDKN2A: Analysis supports interpretation of the p14 and p16 proteins.; CDKN2A (p16INK4a): CDKN2A: Analysis supports interpretation of the p14 and p16 proteins.
EPCAM: Analysis is limited to deletion/duplication analysis.
FH: Sequencing analysis for exons 9 includes only cds +/- 10 bp.
GREM1: Analysis of this gene is limited to deletion/duplication analysis of the promoter region.
MITF: Analysis is limited to the NM_000248.3:c.952G>A p.Glu318Lys variant.
MLH1: Deletion/duplication analysis covers the promoter region.
MSH2: Analysis includes the exon 1-7 inversion (Boland mutation).
PHOX2B: Alanine repeat numbers for the commonly expanded region in exon 3 are not determined.
POLD1: Sequencing analysis for exons 22 includes only cds +/- 10 bp.
SDHA: Deletion/duplication analysis is not offered for this gene. Sequencing analysis for exons 6-8, 14 includes only cds +/- 10 bp.
TP53: Deletion/duplication analysis covers the promoter region.
WRN: Deletion/duplication analysis is not offered for exons 10 or 11.
Resources
Clinical resources
Genes and associated cancers chart Hereditary cancer gene list Hereditary cancer risks and references chart Invitae brochureReferences
- American Society of Clinical Oncology, Cancer. Net Accessed September 2019.
- Cancer Research UK, cancerresearchuk.org. Accessed September 2019.
- Desmond, A, et al. Clinical Actionability of Multigene Panel Testing for Hereditary Breast and Ovarian Cancer Risk Assessment. JAMA Oncol. 2015; :None. PMID: 26270727
- Garber, JE, Offit, K. Hereditary cancer predisposition syndromes. J. Clin. Oncol. 2005; 23(2):276-92. doi: 10.1200/JCO.2005.10.042. PMID: 15637391
- Hall, MJ, et al. Gene panel testing for inherited cancer risk. J Natl Compr Canc Netw. 2014; 12(9):1339-46. PMID: 25190699
- Hampel, H, et al. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet. Med. 2015; 17(1):70-87. doi: 10.1038/gim.2014.147. PMID: 25394175
- Kurian, AW, et al. Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment. J. Clin. Oncol. 2014; 32(19):2001-9. PMID: 24733792
- LaDuca, H, et al. Utilization of multigene panels in hereditary cancer predisposition testing: analysis of more than 2,000 patients. Genet. Med. 2014; 16(11):830-7. PMID: 24763289
- Malkin, D, et al. Predisposition to pediatric and hematologic cancers: a moving target. Am Soc Clin Oncol Educ Book. 2014; :e44-55. PMID: 24857136
- National Cancer Institute, Cancer.gov, Accessed September 2019.
- Robson, ME, et al. American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility. J. Clin. Oncol. 2015; 33(31):3660-7. PMID: 26324357
