FeedbackMassively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray/Sequencing/Multiplex Ligation-dependent Probe Amplification
- Recommended test to confirm a diagnosis of a hereditary cancer syndrome in individuals with personal or family history consistent with features of more than one cancer syndrome.
- When a relative has a previously identified pathogenic sequence variant, see Familial Mutation, Targeted Sequencing (2001961).
Polymerase Chain Reaction/Sequencing
- 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 the genes analyzed by this panel cause variable phenotypes and cancer risks, and have been implicated in hereditary cancer. Hereditary predisposition is often characterized by early age of cancer onset (typically before age 50), and the development of two or more cancers, multifocal cancers, or similar cancers in an individual or in a closely related family member(s). See Genes Tested table below for more details regarding the genes and syndromes included on the Hereditary Cancer Panel.
Disease Overview
Etiology
Approximately 5-10% of cancer is associated with a hereditary cause.
Inheritance
- All genes tested on this panel are autosomal dominant with the exception of:
- SDHD gene: autosomal dominant with paternal parent-of-origin effect
- MAX and SDHAF2 genes: autosomal dominant with possible paternal parent-of-origin effect
- MUTYH gene: 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.
- See table below for additional details.
Test Description
See Genes Tested table for genes included in the panel.
Clinical Sensitivity
Variable, dependent on phenotype/condition
Testing Strategy
- Indications for ordering
- To diagnose a hereditary cancer syndrome in an individual with a personal and/or family history consistent with more than one cancer syndrome
- Contraindications for ordering
- 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 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, MSH3, NF1, RECQL, SMARCA4, WT1
- 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
- RECQL (NM_002907) 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
- 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:
-
Gene Exon(s) APC
(NM_001127511) 1
BAP1
(NM_004656) 1
BARD1
(NM_000465) 1
BMPR1A
(NM_004329) 9
BRCA1
(NM_007300) 13
CDH1
(NM_004360) 1
CDKN2A
(NM_000077) 2
CDKN2A
(NM_058195) 2
CHEK2
(NM_001005735) 3
CHEK2
(NM_007194) 11, 12, 14, 15
FH
(NM_000143) 1
FLCN
(NM_144997) 8
MAX
(NM_001320415) 5
MAX
(NM_145113) 5
MRE11
(NM_005591) 2
MSH2
(NM_000251) 1
MSH2
(NM_001258281) 2
MSH6
(NM_000179) 10
MUTYH
(NM_001128425) 1
NF2
(NM_000268) 7, 13, 16
NTHL1
(NM_002528) 3, 4, 5, 6
PALB2
(NM_024675) 1
POLD1
(NM_002691) 6, 18, 25
PTEN
(NM_000314) 8, 9
PTEN
(NM_001304717) 1
RAD51D
(NM_002878) 1
RB1
(NM_000321) 1
RET
(NM_020975) 1
SDHD
(NM_001276506) 4
SMARCB1
(NM_003073) 5
SUFU
(NM_001178133) 11
SUFU
(NM_016169) 1
TP53
(NM_001126113) 10
TP53
(NM_001126114) 10
TSC2
(NM_000548) 17, 29, 41
VHL
(NM_000551) 1
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 |
|---|---|---|---|
|
ALK |
105590 |
Associated cancer(s)/tumor(s): neuroblastoma, ganglioneuroblastoma, ganglioneuroma |
AD |
|
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 |
|
ATM |
607585 |
Associated cancer(s)/tumor(s): breast, pancreas, ovarian, colorectala |
AD |
|
Ataxia-telangiectasia |
AR |
||
|
ATR |
601215 |
FCTCS Associated cancer(s)/tumor(s): oropharyngeal |
AD |
|
Seckel syndrome 1 |
AR |
||
|
AXIN2 |
604025 |
ODCRCS Associated cancer(s): polyposis, colorectala |
AD |
|
BAP1 |
603089 |
BAP1-TPDS Associated cancer(s)/tumor(s): BAP1-inactivated melanocytic tumors, uveal melanoma, malignant mesothelioma, cutaneous melanoma, renal cell carcinoma, basal cell carcinoma |
AD |
|
BARD1 |
601593 |
Associated cancer(s)/tumor(s): breast a |
AD |
|
BMPR1A |
601299 |
JPS Associated cancer(s)/tumor(s): juvenile polyps, colorectal, stomach, small intestine, pancreas |
AD |
|
BRCA1 |
113705 |
HBOC syndrome Associated cancer(s)/tumor(s): breast, ovarian, prostate, pancreas |
AD |
|
Fanconi anemia, complementation group S |
AR |
||
|
BRCA2 |
600185 |
HBOC syndrome Associated cancer(s)/tumor(s): breast, ovarian, prostate, pancreas, melanoma |
AD |
|
Fanconi anemia, complementation group D1 |
AR |
||
|
BRIP1 |
605882 |
Associated cancer(s)/tumor(s): ovarian, breast a |
AD |
|
Fanconi anemia, complementation group J |
AR |
||
|
CDH1 |
192090 |
HDGC Associated cancer(s)/tumor(s): diffuse gastric, lobular breast |
AD |
|
CDK4 |
123829 |
Associated cancer(s)/tumor(s): cutaneous melanoma |
AD |
|
CDKN1B |
600778 |
MEN Type 4 Associated cancer(s)/tumor(s): parathyroid, pituitary, gastrinoma, insulinoma, gastro-entero-pancreatic (GEP), carcinoid, adrenocortical, nonendocrine |
AD |
|
CDKN2A |
600160 |
FAMMM-PC syndrome (also known as melanoma-pancreatic cancer syndrome) Associated cancer(s)/tumor(s): cutaneous melanoma, pancreas |
AD |
|
CHEK2 |
604373 |
Associated cancer(s)/tumor(s): breast, prostate, colorectal, thyroid a |
AD |
|
DICER1 |
606241 |
DICER1-related disorders Associated cancer(s)/tumor(s): pleuropulmonary blastoma, ovarian sex cord-stromal tumors, cystic nephroma, thyroid |
AD |
|
EPCAM |
185535 |
Lynch syndrome/HNPCC Associated cancer(s)/tumor(s): colorectal, endometrial, stomach, pancreas, ovarian,a breast,a and others |
AD |
|
FH |
136850 |
HLRCC Associated cancer(s)/tumor(s): papillary type 2 renal cancer, cutaneous and uterine leiomyomata |
AD |
|
Fumarase deficiency |
AR |
||
|
FLCN |
607273 |
BHDS Associated cancer(s)/tumor(s): renal |
AD |
|
MAX |
154950 |
Associated cancer(s)/tumor(s): pheochromocytoma, paraganglioma |
ADb |
|
MEN1 |
613733 |
MEN type 1 Associated cancer(s)/tumor(s): parathyroid, pituitary, gastrinoma, insulinoma, carcinoid, adrenocortical |
AD |
|
MET |
164860 |
HPRCC Associated cancer(s)/tumor(s): papillary type 1 renal cancer |
AD |
|
MLH1 |
120436 |
Lynch syndrome/HNPCC Associated cancer(s)/tumor(s): colorectal, endometrial, stomach, ovarian, pancreas, breast,a and others |
AD |
|
CMMRD |
AR |
||
|
MRE11/MRE11A |
600814 |
Associated cancer(s)/tumor(s): breast a |
AD |
|
Ataxia-telangiectasia-like disorder |
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, colorectal a |
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 |
AD |
|
MAP Associated cancer(s)/tumor(s): colorectal adenomas and cancer, duodenal adenomas and cancer |
AR |
||
|
NBN |
602667 |
Associated cancer(s)/tumor(s): breast, ovariana |
AD |
|
NBS |
AR |
||
|
NF1 |
613113 |
NF1 Associated cancer(s)/tumor(s): breast, neurofibromas, gliomas, malignant peripheral nerve sheath tumors, gastrointestinal stromal tumor (GIST), leukemia |
AD |
|
NF2 |
607379 |
NF2 Associated cancer(s)/tumor(s): schwannoma, meningioma |
AD |
|
NTHL1 |
602656 |
Associated cancer(s)/tumor(s): polyposis, colorectal a |
AR |
|
PALB2 |
610355 |
Associated cancer(s)/tumor(s): breast, ovarian, pancreasa |
AD |
|
Fanconi anemia, complementation group N |
AR |
||
|
PHOX2B |
603851 |
CCHS Associated cancer(s)/tumor(s): neuroblastoma, ganglioneuroblastoma, ganglioneuroma |
AD |
|
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, colorectal a |
AD |
|
POLE |
174762 |
PPAP Associated cancer(s)/tumor(s): polyposis, colorectal a |
AD |
|
PTEN |
601728 |
Cowden syndrome/PTEN hamartoma tumor syndrome Associated cancer(s)/tumor(s): breast, endometrial, thyroid, colorectal, renal cell carcinoma |
AD |
|
RAD51C |
602774 |
Associated cancer(s)/tumor(s): ovarian , breasta |
AD |
|
Fanconi anemia, complementation group O |
AR |
||
|
RAD51D |
602954 |
Associated cancer(s)/tumor(s): ovarian, breasta |
AD |
|
RB1 |
614041 |
Retinoblastoma Associated cancer(s)/tumor(s): retinoblastoma, retinoma, pinealoblastoma, osteosarcoma, soft tissue sarcoma, melanoma |
AD |
|
RECQL |
600537 |
Associated cancer(s)/tumor(s): breast a |
AD |
|
RET |
164761 |
MEN2 Associated cancer(s)/tumor(s): medullary thyroid carcinoma, pheochromocytoma, parathyroid adenoma |
AD |
|
SDHAF2 |
613019 |
Associated cancer(s)/tumor(s): paraganglioma |
AD b |
|
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 |
ADc |
|
SMAD4 |
600993 |
JPS, HHT syndrome Associated cancer(s)/tumor(s): juvenile polyps, colorectal, stomach, small intestine, pancreas |
AD |
|
SMARCA4 |
603254 |
Rhabdoid tumor predisposition syndrome Associated cancer(s)/tumor(s): rhabdoid tumor |
AD |
|
SMARCB1 |
601607 |
Rhabdoid tumor predisposition syndrome Associated cancer(s)/tumor(s): rhabdoid tumor |
AD |
|
STK11 |
602216 |
PJS Associated cancer(s)/tumor(s): Peutz-Jeghers-type hamartomatous polyps, breast, colorectal, stomach, small intestine, pancreas, ovarian, testes, lung |
AD |
|
SUFU |
607035 |
NBCCS Associated cancer(s)/tumor(s): basal cell carcinoma, medulloblastoma, fibroma, rhabdomyoma |
AD |
|
TMEM127 |
613403 |
Associated cancer(s)/tumor(s): pheochromocytoma, paraganglioma, GIST, pulmonary chondroma, renal clear cell carcinoma |
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 |
|
TSC1 |
605284 |
TSC Associated cancer(s)/tumor(s): cardiac rhabdomyoma, retinal and other hamartomas, renal angiomyolipoma, SEGA, fibromas |
AD |
|
TSC2 |
191092 |
TSC Associated cancer(s)/tumor(s): cardiac rhabdomyoma, retinal and other hamartomas, renal angiomyolipoma, SEGA, fibromas |
AD |
|
VHL |
608537 |
VHL syndrome Associated cancer(s)/tumor(s): hemangioblastoma, retinal angioma, renal cell carcinoma, pheochromocytoma, neuroendocrine tumors, endolymphatic sac tumors, epididymal and broad ligament cystadenomas |
AD |
|
WT1 |
607102 |
WT1-related Wilms tumor, WAGR syndrome, DDS, Frasier syndrome Associated cancer(s)/tumor(s): Wilms tumor |
AD |
|
aAssociation is suggested but not well-established at this time bPossible paternal parent-of-origin effect cPaternal parent-of-origin effect AD, autosomal dominant; AFAP, attenuated FAP; AR, autosomal recessive; BAP1-TPDS, BAP1 tumor predisposition syndrome; BHDS, Birt-Hogg-Dube syndrome; CCHS, congenital central hypoventilation syndrome; CMMRD, constitutional mismatch repair deficiency; CNS, central nervous system; DDS, Denys-Drash syndrome; FAMM-PC, familial atypical multiple mole melanoma-pancreatic carcinoma; AP, familial adenomatous polyposis; FCTCS, Familial cutaneous telangiectasia and cancer syndrome; GAPPS, gastric adenocarcinoma and proximal polyposis of the stomach; GIST, gastrointestinal stromal tumor; HBOC, hereditary breast and ovarian cancer; HDGC, hereditary diffuse gastric cancer; HHT, hereditary hemorrhagic telangiectasia; HLRCC, hereditary leiomyomatosis and renal cell cancer; HNPCC, hereditary nonpolyposis colorectal cancer; HPRCC, hereditary papillary renal cell carcinoma; JPS, juvenile polyposis syndrome; LFS, Li-Fraumeni syndrome; MAP, MUTYH-associated polyposis; MEN, multiple endocrine neoplasia; NBCCS, nevoid basal cell carcinoma syndrome; NBS, Nijmegan breakage syndrome; NF1, neurofibromatosis type 1; NF2, neurofibromatosis type 2; ODCRCS, oligodontia-colorectal cancer syndrome; PJS, Peutz-Jeghers syndrome; PPAP, polymerase proofreading-associated polyposis; SEGA, subependymal giant cell astrocytoma, TSC, tuberous sclerosis complex; VHL, Von Hippel-Lindau |
|||
GeneReviews - Wilms Tumor Predisposition
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GeneReviews - DICER1-Related Disorders
Doros L, Schultz KA, Stewart DR, et al. DICER1-related disorders. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews, University of Washington; 1993-2021. [Last update: Apr 2020; Accessed: Jun 2020]
GeneReviews - Hereditary Paraganglioma-Pheochromocytoma Syndromes
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GeneReviews - Nevoid Basal Cell Carcinoma Syndrome
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GeneReviews - FH tumor predisposition syndrome
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GeneReviews - Von Hippel-Lindau Syndrome
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GeneReviews - Congenital Central Hypoventilation Syndrome
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