Test Center

My Recent Searches

  • No Recent Search.

My Tests Viewed

  • No Test Viewed.

Hereditary Cancer: Laboratory Support of Risk Assessment and Diagnosis

Hereditary Cancer: Laboratory Support of Risk Assessment and Diagnosis

Clinical Focus

Hereditary Cancer

Laboratory Support of Risk Assessment and Diagnosis

  

Contents

Clinical Background

Table 1: Genes Associated With Hereditary Cancer Syndromes

Individuals Suitable for Testing

Table 2: Cancers That May Trigger Genetic Testing Regardless of Family History

Figure 1: Considerations for Hereditary Cancer Risk Testing

Test Availability

Table 3: Tests Available for Evaluation of Hereditary Cancer Risk

Test Selection

Figure 2: Selecting a Hereditary Cancer Genetic Test

Table 4: Genes Associated with Hereditary Cancer

Test Interpretation

Table 5: Proportion of Hereditary Cancer That Can Be Detected with Genetic Testing

References

Clinical Background [return to contents]

Hereditary cancer, which accounts for about 5% to 10% of all cancers,1 is caused by germline mutations in various genes. Mutations in multiple genes can all cause the same type of hereditary cancer; for example, at least 12 different genes have been linked to hereditary breast cancer. On the other hand, germline mutations in a single gene can, and usually do, increase the risk for more than 1 type of cancer. Mutations in the BRCA1 and BRCA2 genes, for example, are linked to hereditary cancer of the breast, ovary, prostate, pancreas, and skin (melanoma). Genes harboring germline mutations may be linked to various syndromes with increased cancer risk (Table 1).

Table 1. Genes Associated With Hereditary Cancer Syndromes

Gene(s)

Associated Syndrome or Condition

BRCA1, BRCA2

BRCA-related breast and/or ovarian cancer syndrome

CDKN2A, CDK4

Familial atypical multiple mole melanoma syndrome

APC

FAP, AFAP, Gardner and Turcot syndromes

PTEN

PTEN hamartoma tumor syndrome (Cowden syndrome)

CDH1

Hereditary diffuse gastric cancer

BMPR1A, SMAD4

Juvenile polyposis syndrome

TP53

Li-Fraumeni syndrome

MLH1, MSH2, MSH6, PMS2, EPCAM

Lynch syndrome

MEN1

MEN type 1

RET

MEN type 2

MUTYH

MUTYH-associated polyposis

NF1

Neurofibromatosis type 1

STK11

Peutz-Jeghers syndrome

SDHAF2, SDHB, SDHC, SDHD

PGL/PCC syndrome

POLD1, POLE

Polymerase proofreading-associated polyposis

RB1

Retinoblastoma syndrome

VHL

Von Hipple-Lindau syndrome

AFAP, attenuated FAP; FAP, familial adenomatous polyposis; MEN, multiple endocrine neoplasia; PGL/PCC, paraganglioma-pheochromocytoma.

Genetic testing can be used to identify individuals who are at increased risk for hereditary cancer. Guidelines may provide options for decreasing that risk; such options could include increased surveillance, surgery, and/or chemoprevention. Targeted testing for at-risk family members can subsequently be performed. If positive, the family member can take steps to prevent cancer or aid in its early detection. Negative results can reassure the family member and prevent unnecessary increases in surveillance or other preventive measures.

Nevertheless, genetic testing does have limitations. Negative results do not completely rule out an increased risk of hereditary cancer, especially when the familial mutation is unknown. Variants with unknown clinical significance may also be detected.

The remainder of this Clinical Focus will provide guidance for selecting individuals appropriate for hereditary cancer risk assessment and testing, along with information to help with test selection and interpretation. The information is applicable to the most common types of hereditary cancer (breast, colon, endometrial, ovarian, pancreatic, and prostate cancer) as well as to other types.

Individuals Suitable for Testing [return to contents]

Individuals suitable for testing are identified by performing a thorough hereditary cancer risk assessment. The National Comprehensive Cancer Network (NCCN) and other organizations provide guidelines for such an assessment.2-4 The recommended assessment includes a personal and family history of cancer that details the type and number of primary cancer(s), age at onset for each cancer, the individual's relationship to affected family members, and their maternal vs paternal lineage. Cancers in first-, second-, and third-degree relatives should be documented. Factors that lower the threshold for genetic testing should be noted; these include Ashkenazi Jewish ancestry, small family size, and adoption. Prior genetic test results from the individual or blood relatives should also be noted. All of the information should be updated periodically, as subsequent information may affect a person's risk.

Individuals with certain cancers should be considered for genetic testing regardless of family history (Table 2). These cancers have a relatively high potential for a hereditary cause; if a mutation is found in the affected individual, testing and preventive options are available for family members. Additional factors that trigger consideration of genetic testing are shown in Figure 1.

Table 2. Cancers That May Trigger Genetic Testing Regardless of Family History3,5

Cancer Type

Associated Gene

Triple negative (ER/PR/HER2 negative) breast cancer

BRCA1, BRCA2

Ovarian, fallopian tube, or primary peritoneal cancer

BRCA1, BRCA2

Endometrial cancer demonstrating mismatch repair deficiency

MLH1, MSH2, MSH6, PMS2, EPCAM

Colorectal cancer demonstrating mismatch repair deficiency

MLH1, MSH2, MSH6, PMS2, EPCAM

Multiple gastrointestinal polyps in children

APC, BMPR1A, EPCAM, MLH1, MSH2, MSH6, MYH, PMS2, PTEN, SMAD4, STK11

Endocrine cancers

    Adrenocortical

    Pheochromocytoma or paraganglioma

    Medullary thyroid


 
TP53

VHL, RET, SDH

RET

Choroid plexus brain cancer

TP53

Retinal or cerebellar hemangioblastoma, endolymphatic sac tumor

VHL

Juvenile myelomonocytic leukemia, optic pathway or peripheral nerve sheath cancer in children

NF1

Figure 1. Considerations for Hereditary Cancer Risk Testing

Per guidelines, individuals who are suitable for testing have undergone genetic counseling, understand the benefits and risks of testing, and agree to be tested.5 When possible, genetic testing should begin with an affected family member with the highest likelihood of carrying a mutation (ie, youngest age at diagnosis, has bilateral or multiple primary cancers, has other related cancers, is most closely related to the patient).2,4 Testing unaffected individuals should only be considered when there is no affected family member available for testing.2,4 An individual with negative or inconclusive test results may be tested again when tests for additional mutations and/or genes become available.

Test Availability [return to contents]

Quest Diagnostics offers an extensive menu of tests that can be used to assess risk of hereditary cancer. Most, but not all, of these tests are listed in Table 3. A complete list can be found at QuestVantage.com. The table is provided for informational purposes only and is not intended as medical advice. A physician's test selection and interpretation, diagnosis, and patient management decisions should be based on his/her education, clinical expertise, and assessment of the patient.

The tests listed include only "clinically actionable" genes, meaning that guidance for patient management is available. The only exception is the MYvantage™ test, which includes 30 actionable genes out of a total of 34 genes tested.

Table 3. Tests Available for Evaluation of Hereditary Cancer Risk

Test Code

Test Name

Clinical Application

BRCA-related Breast and Ovarian Cancer Syndrome

91863

BRCAvantage®, Comprehensivea

Includes detection of point mutations, deletions, and duplications in the BRCA1 and BRCA2 genes.

  • Assess risk for BRCA-related breast and/or ovarian cancer syndrome when there is no known familial mutation
  • Second-tier test to assess risk in Ashkenazi Jewish people who have a negative BRCAvantage®, Ashkenazi Jewish Screen

91864

BRCAvantage®, Ashkenazi Jewish Screena

Includes detection of the 3 founder mutations (c.68_69delAG [185delAG, 187delAG], c.5266dupC [5382insC, 5385insC], and c.5946delT [6174delT]).

  • First-tier test to assess risk for BRCA-related breast and/or ovarian cancer syndrome in Ashkenazi Jewish people with or without a family history of an ethnicity-associated mutation

92140

BRCAvantage®, Ashkenazi Jewish Screen w/Reflex BRCAvantage, Comprehensivea

Includes test code 91864; test code 91863 added with additional charge and CPT code when none of the 3 founder mutations are detected.

  • First- and second-tier tests combined to assess risk for BRCA-related breast and/or ovarian cancer syndrome in Ashkenazi Jewish people with or without a family history of an ethnicity-associated mutation

91866

BRCAvantage®, Rearrangementsa

Includes detection of deletions and duplications in the BRCA1 and BRCA2 genes.

  • Assess risk for BRCA-related breast and/or ovarian cancer syndrome in people who have a negative BRCA1/BRCA2 sequencing test and no, or limited, deletion/duplication study

Lynch Syndrome
Tissue Testing

16767

BRAF Mutation Analysisa

  • Rule out Lynch syndrome in people who show loss of MLH1 IHC stainingb

91332 (91333)

Lynch Syndrome Tumor Panel, IHC with (or without) Interpretationc

Includes MLH1 (70196 or 16967), MSH2 (70197 or 16971), MSH6 (16938 or 16252), and PMS2 (16997 or 16254) protein expression.

  • Screen for Lynch syndrome in patients with colorectal or endometrial cancer
  • Identify MMR gene(s) for mutation testing

14989(X)

Microsatellite Instability (MSI), HNPCCa

  • Screen for Lynch syndrome in patients with colorectal or endometrial cancer

Whole Blood (Mutation) Testing

91461

Lynch Syndrome Panela

Includes detection of point mutations, deletions, and duplications in MLH1, MSH2, MSH6, and PMS2 genes and testing for 3′-EPCAM deletion.

  • Confirm diagnosis of Lynch syndrome in patients with colorectal or endometrial cancer and MSI high/IHC normal (all MMR proteins expressed) test results
  • Assess risk of Lynch syndrome in patients with a Lynch syndrome-related tumor and no previous tumor tissue testing
  • Assess risk of Lynch syndrome in at-risk family members when familial mutation is unknown

91460

Lynch Syndrome, MLH1 Sequencing and Deletion/Duplicationa

  • Confirm diagnosis of Lynch syndrome in patients with 1) loss of MLH1 staining and negative BRAF test and/or 2) loss of PMS2 staining

91471

Lynch Syndrome, MSH2 Sequencing and Deletion/Duplication (Including EPCAM)a

  • Confirm diagnosis of Lynch syndrome in patients with 1) loss of MSH2 staining and/or 2) loss of MSH6 staining

91458

Lynch Syndrome, MSH6 Sequencing and Deletion/Duplicationa

  • Confirm diagnosis of Lynch syndrome in patients with 1) loss of MSH6 staining and/or 2) loss of MSH2 staining

91457

Lynch Syndrome, PMS2 Sequencing and Deletion/Duplicationa

  • Confirm diagnosis of Lynch syndrome in patients with 1) loss of PMS2 staining and/or 2) loss of MLH1 staining
  • Assess risk of Lynch syndrome in at-risk family members when the family mutation is known

Other Single-gene Syndromes or Conditions

93797

APC Sequencing and Deletion/Duplicationa

  • Assess risk or confirm diagnosis of familial adenomatous polyposis (FAP) or attenuated FAP

92568

CDH1 Sequencing and Deletion/Duplicationa

  • Assess risk or confirm diagnosis of hereditary diffuse gastric cancer and/or hereditary breast cancer

92571

PALB2 Sequencing and Deletion/Duplicationa

  • Assess risk or confirm diagnosis of hereditary breast and/or pancreatic cancer

92566

PTEN Sequencing and Deletion/Duplicationa

  • Assess risk or confirm diagnosis of hamartoma tumor syndrome (Cowden syndrome)

93796

RET Sequencing and Deletion/Duplicationa

Includes evaluation of all exons in the RET gene.

  • Assess risk or confirm diagnosis of multiple endocrine neoplasia type 2 and/or familial medullary thyroid carcinoma

92565

STK11 Sequencing and Deletion/Duplicationa

  • Assess risk or confirm diagnosis of Peutz-Jeghers syndrome

92560

TP53 Sequencing and Deletion/Duplicationa

  • Assess risk or confirm diagnosis of Li-Fraumeni syndrome

Hereditary Cancer Panels for Multiple Cancer Types

93791

GIvantage™ Hereditary Colorectal Cancer Panela

Includes detection of point mutations, duplications, and/or deletions in 13 genes: APC, BMPR1A, CDH1, EPCAM, MLH1, MSH2, MSH6, MUTYH, PMS2, PTEN, SMAD4, STK11, and TP53.

  • Assess risk of hereditary cancer in the colon, rectum, and other tissues

93768

MYvantage™ Hereditary Comprehensive Cancer Panela

Includes detection of point mutations, duplications, and/or deletions in 34 genes: APC, ATM, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CDKN2A, CHEK2, EPCAM, MEN1, MLH1, MSH2, MSH6, MUTYH, NBN, NF1, PALB2, PMS2, POLD1, POLE, PTEN, RAD51C, RAD51D, RET, SDHB, SDHC, SDHD, SMAD4, STK11, TP53, and VHL.

  • Assess risk of hereditary cancer in the breast, colon, endometrium, ovary, pancreas, prostate, rectum, neuroendocrine system, and other tissues

Test Selection [return to contents]

If Lynch syndrome is suspected and colorectal or endometrial tumor tissue is available, guidelines recommend tumor testing for microsatellite instability (MSI) and/or MLH1, MSH2, MSH6, and PMS2 protein expression. If these tests reveal a risk for Lynch syndrome, genetic testing is recommended.4 If no tumor tissue is available, guidelines recommend germline genetic testing be considered.4 Refer to the Lynch syndrome Clinical Focus for more information.

The selection of the most appropriate genetic test for hereditary cancer predisposition depends on multiple factors: whether there is a known familial mutation, whether personal and/or familial history suggests a single syndrome, and whether personal and/or family history may be consistent with multiple syndromes. Figure 2 can be used to guide test selection decisions for each of these situations.

Figure 2. Selecting a Hereditary Cancer Genetic Test

Multi-gene panels are a cost-effective and efficient way to detect clinically actionable mutations in appropriately selected patients.2 Their use may increase detection of pathogenic mutations compared to single-gene testing.2 However, there are several issues to consider when selecting such a panel: penetrance of the genes included in the panel, availability of guidelines for risk management (ie, clinical actionability), and increased detection of variants of unknown significance (VUS). Mutations in high-penetrance genes are associated with a 70% to 100% lifetime risk of cancer, while the risk is 30% to 60% for mutations in moderate-penetrance genes.6 Moderate penetrance may be influenced by other genes or environmental factors. Surveillance and risk-reduction guidelines are available for mutations in high penetrance genes and a number of moderate-penetrance genes.2 For other moderate-penetrance genes, guidance for patient management may be less clear and risk management may not be significantly different than that based on family history.2

Detection of VUS is more common in multi-gene testing due to the multiplicity of genes tested and to the limited understanding of the range of normal variation in some of these genes. Increased detection of these variants adds to the complexity of genetic counseling following multi-gene testing.2,7

Table 4 provides a large amount of information to assist with test selection (and interpretation). The table shows which cancers are associated with mutations in a particular gene, which genes are associated with a particular type of cancer, the penetrance (lifetime risk of cancer), and components of the panels offered by Quest Diagnostics. The table is not exhaustive; it does not include associations between genes and cancer types if the literature only supports a possible association. Since research in hereditary cancers is evolving rapidly, the table will need to be updated regularly. For an updated table, please visit the Quest Diagnostics Test Center and/or talk to your Quest sales representative.

Table 4. Genes Associated with Hereditary Cancer

Test Interpretation [return to contents]

Tumor Testing

MSI-low or negative results indicate Lynch syndrome is unlikely, but does not rule it out. Similarly, IHC expression of all 4 of the Lynch syndrome-associated proteins (MLH1, MSH2, MSH6, and PMS2) indicates Lynch syndrome is unlikely. An MSI-high result and/or loss of expression (staining) for a Lynch syndrome-associated protein suggests the patient has Lynch syndrome. These test results should be followed with genetic testing. Refer to the Lynch syndrome Clinical Focus for more information.

Blood (Germline) Testing

A positive result on a genetic test (ie, presence of a known pathogenic or likely pathogenic variant) indicates an increased risk for cancer. The type(s) of cancer will vary based on the gene that contains the variant (Table 4). Further genetic counseling is recommended for the patient. Genetic testing of close family members may be appropriate.

When the familial mutation is known, a negative result (ie, no pathogenic or likely pathogenic variant detected) suggests the patient does not have the familial hereditary cancer or a predisposition for it. Cancer risk is likely to be the same as for the general population. However, a negative result reduces, but does not eliminate, the possibility of having or developing hereditary cancer. Patients with negative results may still harbor rare genetic abnormalities not covered by the test, either in the tested genes or in other cancer susceptibility genes.

Importantly, a negative genetic test result does not mean that the risk for the associated hereditary cancer(s) is negligible. The post-test risk (residual risk) strongly depends on the gene(s) tested and the percentage of hereditary cancer that the gene(s) accounts for. Table 5 includes the known data; however, it is not comprehensive as data are limited at this time.

Table 5. Proportion of Hereditary Cancer That Can Be Detected with Genetic Testing

Hereditary Cancer Type

Gene(s) Tested

Proportion, %

Reference

Breast

BRCA1 and BRCA2

15 – 20

80

Breast

TP53, PTEN, CDH1, STK11,
and PALB2 together

3 – 4

81,82

Diffuse gastric cancer

CDH1

30 – 40

83,84

Melanoma

CDKN2A

38

85

Pediatric adrenocortical cancer
Adult adrenocortical cancer

TP53

50
6

86
87

When the carrier status of affected family members is either negative or unknown, a negative result is not informative. The patient might not have hereditary cancer or may harbor a genetic abnormality not covered by the test, either in the tested genes or in other cancer susceptibility genes. An undetected genetic abnormality may be the cause of the cancer in affected family members.

Genetic counseling that follows a negative genetic test result should include a discussion of the above information, including the residual risk.

A "variant of unknown clinical significance" result indicates the presence of a genetic variant that has not been previously described in the literature or whose significance is unclear based on current evidence. Results should not be used for medical management decisions; rather, decisions should be based on personal and family history. Family studies may help to learn more about the significance of the variant in select cases. Further genetic counseling is recommended for the patient.

Additional assistance in test selection and interpretation of results is available from our Genetic Counselors by calling 1.866.GENE.INFO (1.866.436.3463).

References [return to contents]

  1. Family cancer syndromes. American Cancer Society. http://www.cancer.org/cancer/cancercauses/
    geneticsandcancer/heredity-and-cancer
    . Updated June 25, 2014. Accessed April 20, 2016.

  2. Genetics toolkit. American Society of Clinical Oncology. https://www.asco.org/practice-guidelines/cancer-care-initiatives/genetics-toolkit. Accessed April 20, 2016.

  3. National Comprehensive Cancer Network clinical practice guidelines in oncology (NCCN Guidelines®). Genetic/familial high-risk assessment: colorectal version 1.2016. http://www.nccn.org. Updated June 13, 2016. Accessed June 17, 2016.

  4. National Comprehensive Cancer Network clinical practice guidelines in oncology (NCCN Guidelines®). Genetic/familial high-risk assessment: breast and ovarian version 2.2016. http://www.nccn.org. Updated March 15, 2016. Accessed May 10, 2017.

  5. Committee opinion no. 634: Hereditary cancer syndromes and risk assessment. Obstet Gynecol. 2015;125:1538-1543.

  6. Hall MJ, Forman AD, Pilarski R, et al. Gene panel testing for inherited cancer risk. J Natl Compr Canc Netw. 2014;12:1339-1346.

  7. Robson ME, Bradbury AR, Arun B, et al. American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility. J Clin Oncol. 2015;33:3660-3667.

  8. Antoniou A, Pharoah PD, Narod S, et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet. 2003;72:1117-1130.

  9. Chen S, Parmigiani G. Meta-analysis of BRCA1 and BRCA2 penetrance. J Clin Oncol. 2007;25:1329-1333.

  10. Struewing JP, Hartge P, Wacholder S, et al. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med. 1997;336:1401-1408.

  11. Tai YC, Domchek S, Parmigiani G, et al. Breast cancer risk among male BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst. 2007;99:1811-1814.

  12. Thompson D, Easton DF, Breast Cancer Linkage Consortium. Cancer incidence in BRCA1 mutation carriers. J Natl Cancer Inst. 2002;94:1358-1365.

  13. Breast Cancer Linkage Consortium. Cancer risks in BRCA2 mutation carriers. J Natl Cancer Inst. 1999;91:1310-1316.

  14. Kote-Jarai Z, Leongamornlert D, Saunders E, et al. BRCA2 is a moderate penetrance gene contributing to young-onset prostate cancer: implications for genetic testing in prostate cancer patients. Br J Cancer. 2011;105:1230-1234.

  15. Thompson D, Easton D, Breast Cancer Linkage C. Variation in cancer risks, by mutation position, in BRCA2 mutation carriers. Am J Hum Genet. 2001;68:410-419.

  16. Fitzgerald RC, Hardwick R, Huntsman D, et al. Hereditary diffuse gastric cancer: updated consensus guidelines for clinical management and directions for future research. J Med Genet. 2010;47:436-444.

  17. Hansford S, Kaurah P, Li-Chang H, et al. Hereditary Diffuse Gastric Cancer Syndrome: CDH1 Mutations and Beyond. JAMA Oncol. 2015;1:23-32.

  18. Bubien V, Bonnet F, Brouste V, et al. High cumulative risks of cancer in patients with PTEN hamartoma tumour syndrome. J Med Genet. 2013;50:255-263.

  19. Pilarski R, Stephens JA, Noss R, et al. Predicting PTEN mutations: an evaluation of Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome clinical features. J Med Genet. 2011;48:505-512.

  20. Tan MH, Mester JL, Ngeow J, et al. Lifetime cancer risks in individuals with germline PTEN mutations. Clin Cancer Res. 2012;18:400-407.

  21. Schneider K, Zelley K, Nichols KE, Garber J. Li-Fraumeni syndrome. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews® [Internet]. Seattle, WA; Copyright, University of Washington, Seattle; 1993-2016. http://www.ncbi.nlm.nih.gov/books/NBK1311/. Updated April 11, 2013. Accessed May 17, 2016.

  22. Cybulski C, Kluzniak W, Huzarski T, et al. Clinical outcomes in women with breast cancer and a PALB2 mutation: a prospective cohort analysis. Lancet Oncol. 2015;16:638-644.

  23. Jones S, Hruban RH, Kamiyama M, et al. Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science. 2009;324:217.

  24. Goldgar DE, Healey S, Dowty JG, et al. Rare variants in the ATM gene and risk of breast cancer. Breast Cancer Res. 2011;13:R73.

  25. Roberts NJ, Jiao Y, Yu J, et al. ATM mutations in patients with hereditary pancreatic cancer. Cancer Discov. 2012;2:41-46.

  26. Thompson D, Duedal S, Kirner J, et al. Cancer risks and mortality in heterozygous ATM mutation carriers. J Natl Cancer Inst. 2005;97:813-822.

  27. Cybulski C, Wokolorczyk D, Jakubowska A, et al. Risk of breast cancer in women with a CHEK2 mutation with and without a family history of breast cancer. J Clin Oncol. 2011;29:3747-3752.

  28. Cybulski C, Wokolorczyk D, Kluzniak W, et al. An inherited NBN mutation is associated with poor prognosis prostate cancer. Br J Cancer. 2013;108:461-468.

  29. Naslund-Koch C, Nordestgaard BG, Bojesen SE. Increased risk for other cancers in addition to breast cancer for CHEK2*1100delC heterozygotes estimated from the Copenhagen General Population Study. J Clin Oncol. 2016;34:1208-1216.

  30. Xiang HP, Geng XP, Ge WW, et al. Meta-analysis of CHEK2 1100delC variant and colorectal cancer susceptibility. Eur J Cancer. 2011;47:2546-2551.

  31. Kohlmann W, Gruber SB. Lynch syndrome. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews® [Internet]. Seattle, WA; Copyright, University of Washington, Seattle; 1993-2016. http://www.ncbi.nlm.nih.gov/
    books/NBK1211/
    . Updated May 22, 2014. Accessed June 20, 2016.

  32. Kempers MJ, Kuiper RP, Ockeloen CW, et al. Risk of colorectal and endometrial cancers in EPCAM deletion-positive Lynch syndrome: a cohort study. Lancet Oncol. 2011;12:49-55.

  33. Barrow E, Alduaij W, Robinson L, et al. Colorectal cancer in HNPCC: cumulative lifetime incidence, survival and tumour distribution. A report of 121 families with proven mutations. Clin Genet. 2008;74:233-242.

  34. Bonadona V, Bonaiti B, Olschwang S, et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA. 2011;305:2304-2310.

  35. Choi YH, Cotterchio M, McKeown-Eyssen G, et al. Penetrance of colorectal cancer among MLH1/MSH2 carriers participating in the colorectal cancer familial registry in Ontario. Hered Cancer Clin Pract. 2009;7:14.

  36. Dowty JG, Win AK, Buchanan DD, et al. Cancer risks for MLH1 and MSH2 mutation carriers. Hum Mutat. 2013;34:490-497.

  37. Kastrinos F, Mukherjee B, Tayob N, et al. Risk of pancreatic cancer in families with Lynch syndrome. JAMA. 2009;302:1790-1795.

  38. Moller P, Seppala T, Bernstein I, et al. Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance: first report from the prospective Lynch syndrome database. Gut. 2015

  39. Ramsoekh D, Wagner A, van Leerdam ME, et al. Cancer risk in MLH1, MSH2 and MSH6 mutation carriers; different risk profiles may influence clinical management. Hered Cancer Clin Pract. 2009;7:17.

  40. Stoffel E, Mukherjee B, Raymond VM, et al. Calculation of risk of colorectal and endometrial cancer among patients with Lynch syndrome. Gastroenterology. 2009;137:1621-1627.

  41. van der Post RS, Kiemeney LA, Ligtenberg MJ, et al. Risk of urothelial bladder cancer in Lynch syndrome is increased, in particular among MSH2 mutation carriers. J Med Genet. 2010;47:464-470.

  42. Vasen HF, Stormorken A, Menko FH, et al. MSH2 mutation carriers are at higher risk of cancer than MLH1 mutation carriers: a study of hereditary nonpolyposis colorectal cancer families. J Clin Oncol. 2001;19:4074-4080.

  43. Baglietto L, Lindor NM, Dowty JG, et al. Risks of Lynch syndrome cancers for MSH6 mutation carriers. J Natl Cancer Inst. 2010;102:193-201.

  44. Barrow E, Robinson L, Alduaij W, et al. Cumulative lifetime incidence of extracolonic cancers in Lynch syndrome: a report of 121 families with proven mutations. Clin Genet. 2009;75:141-149.

  45. Hendriks YM, Wagner A, Morreau H, et al. Cancer risk in hereditary nonpolyposis colorectal cancer due to MSH6 mutations: impact on counseling and surveillance. Gastroenterology. 2004;127:17-25.

  46. Talseth-Palmer BA, McPhillips M, Groombridge C, et al. MSH6 and PMS2 mutation positive Australian Lynch syndrome families: novel mutations, cancer risk and age of diagnosis of colorectal cancer. Hered Cancer Clin Pract. 2010;8:5.

  47. Senter L, Clendenning M, Sotamaa K, et al. The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations. Gastroenterology. 2008;135:419-428.

  48. Burt R, Neklason DW. Genetic testing for inherited colon cancer. Gastroenterology. 2005;128:1696-1716.

  49. Syngal S, Brand RE, Church JM, et al. ACG clinical guideline: genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol. 2015;110:223-262; quiz 263.

  50. Aretz S, Genuardi M, Hes FJ. Clinical utility gene card for: MUTYH-associated polyposis (MAP), autosomal recessive colorectal adenomatous polyposis, multiple colorectal adenomas, multiple adenomatous polyps (MAP) - update 2012. Eur J Hum Genet. 2013;21

  51. Sampson JR, Jones N. MUTYH-associated polyposis. Best Pract Res Clin Gastroenterol. 2009;23:209-218.

  52. De Brakeleer S, De Greve J, Loris R, et al. Cancer predisposing missense and protein truncating BARD1 mutations in non-BRCA1 or BRCA2 breast cancer families. Hum Mutat. 2010;31:E1175-1185.

  53. Ramus SJ, Song H, Dicks E, et al. Germline mutations in the BRIP1, BARD1, PALB2, and NBN genes in women with ovarian cancer. J Natl Cancer Inst. 2015;107.

  54. National Comprehensive Cancer Network clinical practice guidelines in oncology (NCCN Guidelines®). Melanoma version 1.2017. http://www.nccn.org. Updated November 10, 2016. Accessed May 10, 2017.

  55. Puntervoll HE, Yang XR, Vetti HH, et al. Melanoma prone families with CDK4 germline mutation: phenotypic profile and associations with MC1R variants. J Med Genet. 2013;50:264-270.

  56. Begg CB, Orlow I, Hummer AJ, et al. Lifetime risk of melanoma in CDKN2A mutation carriers in a population-based sample. J Natl Cancer Inst. 2005;97:1507-1515.

  57. Bishop DT, Demenais F, Goldstein AM, et al. Geographical variation in the penetrance of CDKN2A mutations for melanoma. J Natl Cancer Inst. 2002;94:894-903.

  58. de Snoo FA, Bishop DT, Bergman W, et al. Increased risk of cancer other than melanoma in CDKN2A founder mutation (p16-Leiden)-positive melanoma families. Clin Cancer Res. 2008;14:7151-7157.

  59. McWilliams RR, Wieben ED, Rabe KG, et al. Prevalence of CDKN2A mutations in pancreatic cancer patients: implications for genetic counseling. Eur J Hum Genet. 2011;19:472-478.

  60. Vasen HF, Gruis NA, Frants RR, et al. Risk of developing pancreatic cancer in families with familial atypical multiple mole melanoma associated with a specific 19 deletion of p16 (p16-Leiden). Int J Cancer. 2000;87:809-811.

  61. National Comprehensive Cancer Network clinical practice guidelines in oncology (NCCN Guidelines®). Neuroendocrine tumors version 1.2016. Downloaded from http://www.nccn.org. Updated April 2016. Accessed April 2016.

  62. Giusti F, Marini F, Brandi ML. Multiple endocrine neoplasia type 1. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews® [Internet]. Seattle, WA; Copyright, University of Washington, Seattle; 1993-2016. http://www.ncbi.nlm.nih.gov/books/NBK1538/. Updated February 12, 2015. Accessed April 20, 2016.

  63. Evans DG, Baser ME, McGaughran J, et al. Malignant peripheral nerve sheath tumours in neurofibromatosis 1. J Med Genet. 2002;39:311-314.

  64. Galan SR, Kann PH. Genetics and molecular pathogenesis of pheochromocytoma and paraganglioma. Clin Endocrinol (Oxf). 2013;78:165-175.

  65. Hersh JH, American Academy of Pediatrics Committee on Genetics. Health supervision for children with neurofibromatosis. Pediatrics. 2008;121:633-642.

  66. Madanikia SA, Bergner A, Ye X, et al. Increased risk of breast cancer in women with NF1. Am J Med Genet A. 2012;158A:3056-3060.

  67. Walker L, Thompson D, Easton D, et al. A prospective study of neurofibromatosis type 1 cancer incidence in the UK. Br J Cancer. 2006;95:233-238.

  68. Bellido F, Pineda M, Aiza G, et al. POLE and POLD1 mutations in 529 kindred with familial colorectal cancer and/or polyposis: review of reported cases and recommendations for genetic testing and surveillance. Genet Med. 2016;18:325-332.

  69. Palles C, Cazier JB, Howarth KM, et al. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat Genet. 2013;45:136-144.

  70. Loveday C, Turnbull C, Ruark E, et al. Germline RAD51C mutations confer susceptibility to ovarian cancer. Nat Genet. 2012;44:475-476; author reply 476.

  71. Song H, Dicks E, Ramus SJ, et al. Contribution of germline mutations in the RAD51B, RAD51C, and RAD51D genes to ovarian cancer in the population. J Clin Oncol. 2015;33:2901-2907.

  72. Marquard J, Eng C. Multiple endocrine neoplasia type 2. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews® [Internet]. Seattle, WA; Copyright, University of Washington, Seattle; 1993-2016. http://www.ncbi.nlm.nih.gov/books/NBK1257/. Updated June 25, 2015. Accessed April 20, 2016.

  73. Martucciello G, Lerone M, Bricco L, et al. Multiple endocrine neoplasias type 2B and RET proto-oncogene. Ital J Pediatr. 2012;38:9.

  74. Kirmani S, Young WF. Hereditary paraganglioma-pheochromocytoma syndromes. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews® [Internet]. Seattle, WA; Copyright, University of Washington, Seattle; 1993-2016. http://www.ncbi.nlm.nih.gov/books/NBK1548/. Updated November 6, 2014. Accessed May 17, 2016.

  75. Benn DE, Robinson BG, Clifton-Bligh RJ. 15 years of paraganglioma: clinical manifestations of paraganglioma syndromes types 1-5. Endocr Relat Cancer. 2015;22:T91-103.

  76. Ricketts CJ, Forman JR, Rattenberry E, et al. Tumor risks and genotype-phenotype-proteotype analysis in 358 patients with germline mutations in SDHB and SDHD. Hum Mutat. 2010;31:41-51.

  77. Frantzen C, Klasson TD, Links TP, Giles. Von Hippel-Lindau syndrome. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews® [Internet]. Seattle, WA; Copyright, University of Washington, Seattle; 1993-2016. http://www.ncbi.nlm.nih.gov/books/NBK1463/. Updated August 6, 2015. Accessed May 25, 2016.

  78. Maher ER, Neumann HP, Richard S. von Hippel-Lindau disease: a clinical and scientific review. Eur J Hum Genet. 2011;19:617-623.

  79. Maher ER, Yates JR, Harries R, et al. Clinical features and natural history of von Hippel-Lindau disease. Q J Med. 1990;77:1151-1163.

  80. Breast cancer facts and figures 2013-2014. http://www.cancer.org/acs/groups/content/@research/documents
    /document/acspc-042725.pdf
    . Accessed April 20, 2016.

  81. Couch FJ, Nathanson KL, Offit K. Two decades after BRCA: setting paradigms in personalized cancer care and prevention. Science. 2014;343:1466-1470.

  82. Tischkowitz M, Xia B, Sabbaghian N, et al. Analysis of PALB2/FANCN-associated breast cancer families. Proc Natl Acad Sci U S A. 2007;104:6788-6793.

  83. Hereditary diffuse gastric cancer. Genetics Home Reference. https://ghr.nlm.nih.gov/condition/hereditary-diffuse-gastric-cancer. Reviewed January 2014. Accessed April 20, 2016.

  84. Oliveira C, Suriano G, Ferreira P, et al. Genetic screening for familial gastric cancer. Hered Cancer Clin Pract. 2004;2:51-64.

  85. Goldstein AM, Chan M, Harland M, et al. High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL. Cancer Res. 2006;66:9818-9828.

  86. Wasserman JD, Novokmet A, Eichler-Jonsson C, et al. Prevalence and functional consequence of TP53 mutations in pediatric adrenocortical carcinoma: a children's oncology group study. J Clin Oncol. 2015;33:602-609.

  87. Raymond VM, Else T, Everett JN, et al. Prevalence of germline TP53 mutations in a prospective series of unselected patients with adrenocortical carcinoma. J Clin Endocrinol Metab. 2013;98:E119-125.
     

Content reviewed 05/2017

 

top of page

* The tests listed by specialist are a select group of tests offered. For a complete list of Quest Diagnostics tests, please refer to our Directory of Services.