Hereditary Cancer Panel

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

  • 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).
  • Testing for a known familial sequence variant by sequencing gene of interest. A copy of the family member’s test result documenting the familial gene variant is REQUIRED.
  • To determine if the variant(s) of interest are detectable by this assay, contact an ARUP genetic counselor at 800-242-2787.

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 on other related tests (see Related Tests section and Hereditary Cancer Genetic Testing – Germline Testing for Inherited Cancer Syndromes).

Genetics

Genes

See 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 with the exception of 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.
  • See 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 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

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