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FeedbackMassively Parallel Sequencing/Sequencing/Multiplex Ligation-Dependent Probe Amplification (MLPA)
- 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
- Testing minors for adult-onset conditions is not recommended and testing will not be performed on minors without prior approval; for additional information, please contact an ARUP genetic counselor (800-242-2787).
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 cancer. Hereditary cancer predisposition is often characterized by early age of cancer onset (typically before age 50), and multiple, multifocal, and/or related cancers in a single 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. Genes included on this panel are also included in other ARUP hereditary cancer tests. For more information, refer to the ARUP Hereditary Cancer Panel Comparison table.
Genetics
Genes
Refer to the Genes Tested table for genes included in the panel.
Etiology
Approximately 5-10% of cancer is associated with a hereditary cause.
Inheritance
- All genes tested on this panel are autosomal dominant except for the following:
| Gene | Inheritance Pattern |
|---|---|
| SDHAF2 | Autosomal dominant with paternal parent-of-origin effect |
| SDHD | Autosomal dominant with paternal parent-of-origin effect |
| MAX | Autosomal dominant with possible paternal parent-of-origin effect |
| MUTYH | Autosomal recessive but may also have autosomal dominant risks that are not well-defined |
| MLH3 | Autosomal recessive |
| MSH3 | Autosomal recessive |
| NTHL1 | Autosomal recessive |
| TERT | Both autosomal dominant and autosomal recessive |
- Some genes are associated with autosomal recessive childhood cancer predisposition or other syndromes.
- Refer to the Genes Tested table for additional details.
Test Interpretation
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.
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 polymerase chain reaction (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 genes and exons:
- MSH2 (NM_000251) 5
- PMS2 (NM_000535) 7
- PTEN (NM_000314) 9
- Multiplex ligation-dependent probe amplification (MLPA) is performed on the following gene to call exon-level deletions and duplications:
- PMS2 (NM_000535)
Clinical Sensitivity
Variable, dependent on phenotype/condition
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 multiplex ligation-dependent probe amplification (MLPA) unless otherwise indicated. bVariants greater than 10 bp may be detected, but the analytical 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 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
- 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
- CHEK2 (NM_001005735) 3; (NM_001349956) 4
- FLCN (NM_001353229) 7
- MEN1 (NM_001370251) 8
- MITF (NM_001354607) 2
- PDGFRA (NM_001347827) 17; (NM_001347828) 2; (NM_001347830) 1
- RECQL (NM_002907) 14,15; (NM_032941) 15,16
- SDHA (NM_004168) 14; (NM_001294332) 13; (NM_001330758) 12
- SDHC (NM_001035511) partial exon 5 (Chr1:161332225-161332330); (NM_001278172) partial exon 4 (Chr1:161332225-161332330)
- SDHD (NM_001276506) 4
- VHL (NM_001354723) 2
- The following may not be detected:
- Deletions/duplications/insertions of any size by massively parallel sequencing
- 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 and/or repetitive/homologous regions
- Low-level somatic variants
- The following regions may have reduced sequencing sensitivity due to technical limitations of the assay:
- RB1 (NM_000321) exon 22
- SUFU (NM_016169, NM_001178133) exon 1
- Deletions/duplications in the following exons:
Gene Exon(s) APC (NM_001354896) 12; (NM_001354898, NM_001354904) 2; (NM_001354900) 11 BMPR1A (NM_004329) 12-13 BRCA1 (NM_007294, NM_007299, NM_007300) 2; (NM_007298) 1 CDH1 (NM_001317185) 10 CDKN2A (NM_000077, NM_001195132, NM_001363763, NM_058195) 2 CHEK2 (NM_007194) 11-15; (NM_001005735) 3,12-16; (NM_001257387) 12-16; (NM_001349956) 4,10-14; (NM_145862) 10-14 CTNNA1 (NM_001290307) 19; (NM_001324002, NM_001324004) 13; (NM_001324003) 15; (NM_001324005) 16 FLCN (NM_001353229) 7 MEN1 (NM_001370251) 8 MITF (NM_001354607) 2 MLH3 (NM_001040108) 7-8; (NM_014381) 7 PDGFRA (NM_001347827) 17; (NM_001347828) 2; (NM_001347830) 1 PTEN (NM_000314, NM_001304718) 9; (NM_001304717) 1,10 RB1 (NM_000321) 22 RECQL (NM_002907) 14-15; (NM_032941) 15-16 SDHA (NM_004168) 1,10-15; (NM_001294332) 1,9-14; (NM_001330758) 1,10-13 SDHD (NM_001276506) 4 SMARCE1 (NM_003079) 7,10-11 VHL (NM_001354723) 2
Genes Tested
To compare directly to other hereditary cancer panels offered by ARUP Laboratories, see the ARUP Hereditary Cancer Panel Comparison table.
| Gene | MIM Number | Disorder/Associated Cancer(s)/Tumor(s) | Inheritance |
|---|---|---|---|
| ALK | 105590 | ALK-related neuroblastic tumor susceptibility Ganglioneuroblastoma, ganglioneuroma, neuroblastoma | AD |
| 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 | ||
| AXIN2 | 604025 | ODCRCS Colorectal,a polyposis | AD |
| BAP1 | 603089 | BAP1-TPDS BAP1-inactivated melanocytic tumors, basal cell carcinoma, cutaneous melanoma, malignant mesothelioma, renal cell carcinoma, uveal melanoma | AD |
| BARD1 | 601593 | Breast | AD |
| BMPR1A | 601299 | JPS Colorectal, juvenile polyps, small intestine, stomach | AD |
| 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 | ||
| BRIP1 | 605882 | Breast,a ovarian | AD |
| Fanconi anemia, complementation group J | AR | ||
| CDC73 | 607393 | CDC73-related disorders Hyperparathyroidism-jaw tumor syndrome Hyperparathyroidism/parathyroid carcinoma, kidney lesions/tumors | AD |
| CDH1 | 192090 | HDGC Diffuse gastric, lobular breast | AD |
| CDK4 | 123829 | Cutaneous melanoma, pancreatica | AD |
| CDKN1B | 600778 | MEN Type 4 Gastrinoma, GEP, nonendocrine. parathyroid, pituitary | AD |
| CDKN2A | 600160 | FAMMM-PC syndrome (also known as melanoma-pancreatic cancer syndrome) Cutaneous melanoma, pancreatic | AD |
| CHEK2 | 604373 | Breast, colorectal, prostate, thyroid a | AD |
| CTNNA1 | 116805 | Breast,a stomach | AD |
| DICER1 | 606241 | DICER1-related disorders Pleuropulmonary blastoma, ovarian sex cord-stromal tumors, cystic nephroma, thyroid | AD |
| EGFR | 131550 | Lung | 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 |
| FH | 136850 | FH tumor predisposition syndrome/HLRCC Cutaneous and uterine leiomyomata, papillary type 2 renal cancer, paraganglioma, pheochromocytoma | AD |
| Fumarase deficiency | AR | ||
| FLCN | 607273 | BHDS Fibrofolliculomas, pulmonary cysts/history of pneumothorax, renal cancer | AD |
| HOXB13 | 604607 | Prostate | AD |
| HRAS | 190020 | Costello syndrome Neuroblastoma, rhabdomyosarcoma, transitional cell carcinoma of the bladder | AD |
| KIT | 164920 | GIST | AD |
| LZTR1 | 600574 | Schwannomatosis | AD |
| Noonan syndrome | AR | ||
| MAX | 154950 | HPP syndromes Paraganglioma, pheochromocytoma | ADb |
| MC1R | 155555 | Cutaneous melanomaa | AD |
| MEN1 | 613733 | MEN type 1 Adrenocortical, carcinoid, GEP, neuroendocrine tumors, meningioma, parathyroid, pituitary, thyroid | AD |
| MET | 164860 | HPRCC Papillary type 1 renal cancer | AD |
| MITF | 156845 | Waardenburg syndrome type II Cutaneous melanoma | |
| MLH1 | 120436 | Lynch syndrome/HNPCC Brain, colorectal, endometrial, ovarian, pancreas, prostate, renal pelvis and/or ureter, stomach, and others | AD |
| CMMRD | AR | ||
| MLH3 | 604395 | MLH3-associated polyposis Breast,a colorectal,a polyposis | AD |
| MSH2 | 609309 | Lynch syndrome/HNPCC Brain, colorectal, endometrial, ovarian, pancreas, prostate, renal pelvis and/or ureter, stomach, and others | AD |
| CMMRD | AR | ||
| MSH3 | 600887 | Colorectal,a polyposis | AR |
| MSH6 | 600678 | Lynch syndrome/HNPCC Brain, colorectal, endometrial, ovarian, pancreas, prostate, renal pelvis and/or ureter, stomach, and others | AD |
| CMMRD | AR | ||
| MUTYH | 604933 | Breast,a colorectala | AD |
MAP Colorectal adenomas and cancer, duodenal adenomas and cancer | AR | ||
| NBN | 602667 | Breast,a ovarian,a prostatea | AD |
| NBS | AR | ||
| NF1 | 613113 | NF1 Breast, GIST, gliomas, leukemia, malignant peripheral nerve sheath tumors, neurofibromas, pheochromocytoma | AD |
| NF2 | 607379 | NF2 Astrocytoma, ependymoma, meningioma, schwannoma | AD |
| NTHL1 | 602656 | Colorectal,a polyposis | AR |
| PALB2 | 610355 | Breast, ovarian, pancreas, prostate | AD |
| Fanconi anemia, complementation group N | AR | ||
| PDGFRA | 173490 | GIST, inflammatory fibroid polyp, fibroid tumor | AD |
| PMS2 | 600259 | Lynch syndrome/HNPCC Brain, colorectal, endometrial, ovarian, pancreas, prostate, renal pelvis and/or ureter, stomach, and others | AD |
| CMMRD | AR | ||
| POLD1 | 174761 | PPAP Colorectal,a polyposis | AD |
| POLE | 174762 | PPAP Colorectal,a polyposis | AD |
| POT1 | 606478 | POT1 tumor predisposition syndrome Angiosarcoma, chronic lymphocytic leukemia, cutaneous melanoma, glioma | AD |
| PRKAR1A | 188830 | Carney complex Endocrine tumor or overactivity, myxoma, schwannoma | AD |
| PTCH1 | 601309 | NBCCS/Gorlin syndrome Basal cell carcinoma, cardiac and ovarian fibromas, medulloblastoma | AD |
| PTEN | 601728 | Cowden syndrome/PTEN hamartoma tumor syndrome Breast, colorectal, endometrial, Lhermitte-Duclos disease (cerebellar dysplastic gangliocytoma), melanoma a, renal cell carcinoma, thyroid, and others | AD |
| RAD51C | 602774 | Breast, ovarian | AD |
| Fanconi anemia, complementation group O | AR | ||
| RAD51D | 602954 | Breast, ovarian, prostate | AD |
| RB1 | 614041 | Hereditary retinoblastoma Melanoma,a osteosarcoma, pinealoblastoma, retinoblastoma, retinoma, soft tissue sarcoma | AD |
| RECQL | 600537 | Breasta | AD |
| RET | 164761 | MEN2 Medullary thyroid carcinoma, parathyroid adenoma or hyperplasia, pheochromocytoma | AD |
| SDHA | 600857 | HPP syndromes GIST, paraganglioma, pheochromocytoma, pulmonary chondroma, renal clear cell carcinoma | AD |
| SDHAF2 | 613019 | HPP syndromes Paraganglioma | ADc |
| SDHB | 185470 | HPP syndromes GIST, paraganglioma, pheochromocytoma, pulmonary chondroma, renal clear cell carcinoma | AD |
| SDHC | 602413 | HPP syndromes GIST, paraganglioma, pheochromocytoma, pulmonary chondroma, renal clear cell carcinoma | AD |
| SDHD | 602690 | HPP syndromes GIST, paraganglioma, pheochromocytoma, pulmonary chondroma, renal clear cell carcinoma | ADc |
| SMAD4 | 600993 | JPS, HHT syndrome Colorectal, juvenile polyps, small intestine, stomach | AD |
| SMARCA4 | 603254 | Coffin-Siris syndrome, RTPS Rhabdoid tumors located in CNS, kidney, ovary (SCCOHT), and others | AD |
| SMARCB1 | 601607 | Coffin-Siris syndrome, RTPS Associated cancer(s)/tumor(s): Associated cancer(s)/tumor(s): rhabdoid tumors located in: CNS, kidney, and others; schwannomatosis | AD |
| SMARCE1 | 603111 | Coffin-Siris syndrome Meningioma | 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 |
| SUFU | 607035 | NBCCS/Gorlin syndrome Basal cell carcinoma, cardiac and ovarian fibromas, medulloblastoma | AD |
| TERT | 187270 | Dyskeratosis congenita Acute myelogenous leukemia, melanoma,a pulmonary fibrosis | AD and AR |
| TMEM127 | 613403 | HPP syndromes Paraganglioma, pheochromocytoma, renal clear cell carcinoma | 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 |
| TSC1 | 605284 | TSC Cardiac rhabdomyoma, fibromas, renal angiomyolipoma, retinal and other hamartomas, SEGA, and others | AD |
| TSC2 | 191092 | TSC Cardiac rhabdomyoma, fibromas, renal angiomyolipoma, retinal and other hamartomas, SEGA, 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 |
| WT1 | 607102 | WT1 disorder Gonadoblastoma, 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 familial adenomatous polyposis; AR, autosomal recessive; BAP1-TPDS, BAP1 tumor predisposition syndrome; BHDS, Birt-Hogg-Dube syndrome; CMMRD, constitutional mismatch repair deficiency; CNS, central nervous system; DDS, Denys-Drash syndrome; FAMM-PC, familial atypical multiple mole melanoma-pancreatic carcinoma; FAP, familial adenomatous polyposis; FCTCS, Familial cutaneous telangiectasia and cancer syndrome; GAPPS, gastric adenocarcinoma and proximal polyposis of the stomach; GEP, gastro-entero-pancreatic, 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; HPP, hereditary paraganglioma-pheochromocytoma; 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; RTPS, rhabdoid tumor predisposition syndrome; SEGA, subependymal giant cell astrocytoma, TSC, tuberous sclerosis complex; VHL, Von Hippel-Lindau | |||
References
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NCI - Genetic testing for inherited cancer susceptibility syndromes
National Cancer Institute. Genetic testing for inherited cancer susceptibility syndromes. Reviewed March 2019; accessed May 2022.
To compare directly to other hereditary cancer panels offered by ARUP Laboratories, see the ARUP Hereditary Cancer Panel Comparison table.