Hereditary Cancer Panel

Indication for testing:

  • 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).

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.

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

Additional Resources