Disclaimer: The practice guidelines of the American College of Medical Genetics and Genomics (ACMG) and the National Society of Genetic Counselors (NSGC) are developed by members of the ACMG and NSGC to assist medical geneticists, genetic counselors, and other health-care providers in making decisions about appropriate management of genetic concerns, including access to and/or delivery of services. Each practice guideline focuses on a clinical or practice-based issue and is the result of a review and analysis of current professional literature believed to be reliable. As such, information and recommendations within the ACMG and NSGC joint practice guidelines reflect the current scientific and clinical knowledge at the time of publication, are current only as of their publication date, and are subject to change without notice as advances emerge. In addition, variations in practice, which take into account the needs of the individual patient and the resources and limitations unique to the institution or type of practice, may warrant approaches, treatments, and/or procedures that differ from the recommendations outlined in this guideline. Therefore, these recommendations should not be construed as dictating an exclusive course of management, nor does the use of such recommendations guarantee a particular outcome. Genetic counseling practice guidelines are never intended to displace a health-care provider’s best medical judgment based on the clinical circumstances of a particular patient or patient population. Practice guidelines are published by the ACMG or the NSGC for educational and informational purposes only, and neither the ACMG nor the NSGC “approve” or “endorse” any specific methods, practices, or sources of information.
Cancer genetic consultation is an important aspect of the care of individuals at increased risk of a hereditary cancer syndrome. Yet several patient, clinician, and system-level barriers hinder identification of individuals appropriate for cancer genetics referral. Thus, the purpose of this practice guideline is to present a single set of comprehensive personal and family history criteria to facilitate identification and maximize appropriate referral of at-risk individuals for cancer genetic consultation. To develop this guideline, a literature search for hereditary cancer susceptibility syndromes was conducted using PubMed. In addition, GeneReviews and the National Comprehensive Cancer Network guidelines were reviewed when applicable. When conflicting guidelines were identified, the evidence was ranked as follows: position papers from national and professional organizations ranked highest, followed by consortium guidelines, and then peer-reviewed publications from single institutions. The criteria for cancer genetic consultation referral are provided in two formats: (i) tables that list the tumor type along with the criteria that, if met, would warrant a referral for a cancer genetic consultation and (ii) an alphabetical list of the syndromes, including a brief summary of each and the rationale for the referral criteria that were selected. Consider referral for a cancer genetic consultation if your patient or any of their first-degree relatives meet any of these referral criteria.
Genet Med advance online publication 13 November 2014
Cancer genetic consultation services include the evaluation of patients’ personal and family history for concerning features of hereditary cancer predisposition syndromes, development of a differential diagnosis for one or more possible hereditary cancer syndromes, genetic testing if indicated and available, recommendations for management, cancer surveillance and prevention, and information regarding genetic counseling and genetic testing for at-risk relatives. This counseling is informed by the genetic risk assessment or diagnosis, which typically includes personal and family history, genetic and other laboratory results, results from procedures and imaging studies, and physical examination findings. Genetic counseling is an important component of the genetic consultation; it entails a discussion about the clinical and genetic aspects of a suspected diagnosis—including the mode of inheritance, identification of family members at risk, and discussion of the benefits, risks, and limitations of genetic testing and the alternative to not test—and helps patients make informed decisions about genetic testing considering their health-care needs, preferences, and values. Genetic testing performed without pre- and posttest genetic counseling by qualified clinicians has been associated with negative patient and societal outcomes such as misinterpretation of genetic test results, inappropriate medical management, lack of informed decision making, violation of established ethical standards, adverse psychosocial outcomes, and costly, unnecessary genetic testing.1,2,3
Cancer genetic consultation is an important aspect of the care of individuals at increased risk of a hereditary cancer syndrome.4,5,6,7,8 Yet, several patient, clinician, and system-level barriers hinder the identification of individuals appropriate for cancer genetics referral. In addition to limited time for the clinician to collect family history necessary to trigger a referral9,10,11 and limited patient awareness of their family cancer history,12 identifying appropriate patients is complicated by an abundance of complex criteria and guidelines that often differ from each other.13 Thus, the purpose of this practice guideline is to present a single set of comprehensive personal and family history criteria to facilitate identification and maximize appropriate referral of at-risk individuals for cancer genetic consultation. The criteria in this guidance statement are not designed to dictate what, if any, genetic testing is indicated or to recommend any specific cancer screening or treatment management.
Health-care providers have been encouraged to take a thorough family history from their patients and to refer them to genetic providers if the history is suspicious for a hereditary condition. Determining whom to refer is difficult for clinicians who do not specialize in cancer genetics, who may rarely encounter these syndromes, and who may not be familiar with the types of cancers known to be associated with a particular syndrome. These referral guidelines were developed in a table format so that the health-care provider can simply look up the cancer(s) that have been reported in a family and determine whether the personal or family history meets any of the criteria that warrant a referral. We include a short summary of each syndrome that explains the rationale behind the referral criteria in the Recommendations section of this guideline.
Materials and Methods
To develop this guideline, a literature search for each of the hereditary cancer susceptibility syndromes described below was conducted using PubMed. In addition, GeneReviews (http://www.genereviews.org) and the National Comprehensive Cancer Network guidelines (http://www.nccn.org/professionals/physician_gls/f_guidelines.asp) were reviewed when applicable. The searches were conducted between 1 December 2012 and 20 June 2013 and included the following search terms: hereditary cancer syndromes, referral criteria, guidelines, testing, mutation likelihood, and each syndrome’s specific name. When conflicting guidelines were identified, the following processes were used to select the referral criteria for inclusion in this practice guideline. We ranked the sources of the differing guidelines. Position papers from national and professional organizations ranked highest, followed by consortium guidelines and then peer-reviewed publications from single institutions. When guidelines from national and professional organizations differed, an attempt was made to select the least restrictive (i.e., most inclusive) set of referral criteria, as long as we felt it would not result in too many inappropriate referrals. For example, the National Comprehensive Cancer Network offers both evaluation criteria and genetic testing criteria for hereditary breast–ovarian cancer syndrome. We believe that the evaluation guidelines would result in an unmanageable number of referrals with little yield to patients and therefore chose the National Comprehensive Cancer Network genetic testing recommendations.
The criteria for cancer genetic consultation referral are detailed in Tables 1 and 2 . Table 1 includes an alphabetical list of common cancers along with the criteria that, if met, would warrant a referral for a cancer genetic consultation. Table 2 includes the same information based on an alphabetical list of rare cancers. Referring to the tables in the clinic when a cancer is noted in a family history may be helpful to quickly determine whether a referral is indicated. If the family or individual meets the referral guideline for a particular syndrome, a brief summary of the syndrome and the rationale for the referral criteria can be found listed alphabetically in the text below. More detailed information about these syndromes can be found elsewhere.14
Consider referral for a cancer genetic consultation if your patients or any of their first-degree relatives meet any of these criteria. All affected relatives must be on the same side of the family. For the purposes of these guidelines, close relatives include first-degree relatives such as parents, siblings, and children, and second-degree relatives such as aunts, uncles, nieces, nephews, grandparents, and grandchildren. Please note that all the syndromes described in this guideline are inherited in an autosomal dominant manner, except where otherwise noted. Finally, any individual in a family with a known mutation in a cancer susceptibility gene should be referred for cancer genetic consultation.
Birt–Hogg–Dubé syndrome (OMIM 135150)
Birt–Hogg–Dubé syndrome is caused by mutations in the FLCN gene and is characterized by the presence of classic skin lesions (fibrofolliculomas, perifollicular fibromas, trichodiscomas or angiofibromas, and acrochordons), bilateral and multifocal renal tumors (chromophobe clear cell renal carcinoma, renal oncocytoma, oncocytic hybrid tumor, and less often, clear cell renal carcinoma), and multiple bilateral lung cysts often associated with spontaneous pneumothorax.15 Skin lesions typically occur in the 30s and 40s and increase with age. The median age at diagnosis of renal cell tumors is 48 years, with a range of 31–71 years.
Referral should be considered for any individual with a personal history of or first-degree relative with (i) ≥5 Birt–Hogg–Dubé–associated facial or truncal papules; (ii) early-onset (<50 years old), bilateral or multifocal clear cell renal carcinoma; (iii) renal cancers with Birt–Hogg–Dubé histology (chromophobe, oncocytoma, or oncocytic hybrid); or (iv) lung cysts associated with multiple spontaneous pneumothoraxes.16,17
Carney complex (OMIM 160980)
Carney complex is caused by mutations in the PRKAR1A gene and is characterized by pale brown to black lentigenes; myxomas of the heart, skin, and breast; primary pigmented nodular adrenocortical disease; and large cell calcifying Sertoli cell tumors. Psammomatous melanotic schwannoma, a rare nerve sheath tumor, can also occur. At least 50% of individuals with isolated primary pigmented nodular adrenocortical disease have a PRKAR1A mutation.18,19,20 Thus, isolated primary pigmented nodular adrenocortical disease is sufficient for referral to genetic consultation. PRKAR1A mutations are found in 71% of individuals with at least two major diagnostic criteria for Carney complex18 ( Table 3 ).
Referral should be considered for any individual with a personal history of or first-degree relative with (i) primary pigmented nodular adrenocortical disease or (ii) two or more diagnostic criteria21 ( Table 3 ).
Constitutional mismatch repair deficiency (OMIM 276300)
Constitutional mismatch repair deficiency is a recessive condition caused by biallelic mutations in the mismatch repair genes (MLH1, MSH2 (including methylation due to an EPCAM deletion), MSH6, and PMS2) and is characterized by a high risk of developing cancers during childhood, including Lynch syndrome (LS)–associated cancers, hematologic malignancies, and embryonic tumors.22 Individuals with constitutional mismatch repair deficiency have neurofibromatosis type 1–like features, with café-au-lait macules observed in most cases23 and skinfold freckling, Lisch nodules, neurofibromas, and tibial pseudoarthosis reported in fewer cases. Individuals with constitutional mismatch repair deficiency do not always have a family history of cancer.
Referral should be considered for any individual with a personal history of or first-degree relative with (i) an LS-associated cancer in childhood or (ii) another type of childhood cancer and one or more of the following features: (i) café-au-lait macules, skinfold freckling, Lisch nodules, neurofibromas, tibial pseudoarthrosis, or hypopigmented skin lesions; (ii) family history of LS-associated cancer; (iii) a second primary cancer; (iv) a sibling with a childhood cancer; or (v) consanguineous parents.
Cowden syndrome, also known as PTEN hamartoma tumor syndrome (OMIM 158350)
Cowden syndrome is caused by mutations in the PTEN gene and is characterized by benign skin findings, increased lifetime risks for breast (30–85%; often early-onset), follicular thyroid (10–38%), renal cell (34%), endometrial (5–28%), and colorectal cancers (9%), and possibly melanoma (6%).24,25,26,27,28 Clinical diagnostic criteria involve combinations of major and minor criteria29 ( Table 4 ). We recommend referral for anyone meeting any three criteria from the major or minor diagnostic criteria.
Referral should be considered for any individual with a personal history of or first-degree relative with (i) Lhermitte–Duclos disease diagnosed after age 18 (ref. 30) or (ii) any three criteria from the major or minor diagnostic criteria list in the same person31 ( Table 4 ).
Familial adenomatous polyposis and attenuated familial adenomatous polyposis (OMIM 175100)
Familial adenomatous polyposis (FAP) and attenuated FAP are caused by mutations in the APC gene and are characterized by adenomatous colon polyps and increased lifetime risk for colorectal cancer (nearly 100% for individuals with FAP and 70% for individuals with attenuated FAP).32 A clinical diagnosis of classic FAP is made when an individual has >100 adenomatous polyps in his or her colon. Attenuated FAP is characterized by 30–100 adenomatous polyps. Individuals with FAP are also at increased risk for duodenal (4–12%), pancreatic (~2%), and papillary thyroid (cribriform morular variant)33,34 (1–2%)29,30 cancers, as well as hepatoblastoma by age 5 (1–2%)35,36 and medulloblastoma (<1%).32 Extracolonic manifestations can include congenital hypertrophy of the retinal pigmented epithelium, osteomas, dental abnormalities, benign cutaneous lesions such as epidermoid cysts and fibromas, and desmoid tumors. APC mutations are found in 80% of patients with 1,000 or more adenomas, 56% of patients with 100–999 adenomas, 10% of patients with 20–99 adenomas, and 5% of patients with 10–19 adenomas.37
Referral should be considered for any individual with a personal history of or first-degree relative with (i) a total of ≥10 adenomatous colon polyps with or without a colorectal or other FAP-associated cancer38; (ii) a cribriform morular variant of papillary thyroid cancer; (iii) a desmoid tumor; or (iv) hepatoblastoma diagnosed before age 5.
Familial gastrointestinal stromal tumor (OMIM 606764)
Familial gastrointestinal stromal tumor (GIST) is a rare condition associated with mutations in the KIT, PDGFRA, SDHB, and SDHC genes. Individuals with germline mutations in KIT can have hyperpigmentation, mast cell tumors, or dysphagia. Large hands have been associated with PDGFRA mutations. Individuals with neurofibromatosis type 1 can also develop GISTs. Wild-type GISTs are defined as GISTs that do not have detectable mutations in KIT, PDGFRA, or BRAF. Of patients with sporadic wild-type GIST, 12% had SDHB or SDHC mutations,39 and in another series, 12% of wild-type GISTs had an SDHA mutation (all of which exhibited loss of the SDHA protein by immunohistochemistry).40 There are no published referral guidelines for this condition; recommendations were made based on expert opinion.
Referral should be considered for any individual with a personal history of or first-degree relative with (i) three or more close relatives with GIST; (ii) wild-type GIST; or (iii) individuals with three or more GISTs.
Familial pancreatic cancer (OMIM 260350)
Pancreatic cancer risk is increased in several known hereditary cancer syndromes such as Lynch syndrome, Peutz–Jeghers syndrome, FAP, hereditary melanoma, and hereditary breast–ovarian cancer syndrome. The most common cause of familial pancreatic cancer are mutations in the BRCA2 gene. Published studies of families with two or more pancreatic cancer diagnoses demonstrate that 2.8–17% of these families have a BRCA2 gene mutation.41,42,43,44 Because of increased prevalence of BRCA mutations, unselected individuals of Ashkenazi Jewish ancestry with pancreatic cancer have a 5.5–31% chance of having one of the three Ashkenazi Jewish founder mutations.45,46,47 Some families with familial pancreatic cancer also have mutations in the CDKN2A, PALB2, or ATM genes. PALB2 mutations occur in 0.9–3.7% of pancreatic cancer patients with at least one additional relative affected with pancreatic cancer.48,49,50 ATM mutations were found in 2.4% (4/166) of patients with familial pancreatic cancer and in 4.6% (4/87) of families with three or more affected individuals.51
Referral should be considered for any individual with a personal history of or first-degree relative with (i) Ashkenazi Jewish ancestry and pancreatic cancer at any age; (ii) pancreatic cancer and a close relative with pancreatic cancer; (iii) three or more cases of breast, ovarian, pancreatic, and/or aggressive prostate cancer; or (iv) three or more cases of pancreatic cancer and/or melanoma.
Familial prostate cancer (OMIM 176807, 601518, 602759, 300147, 603688, 608656, and 153622)
The genetic etiology of familial prostate cancer has proven difficult to characterize. Autosomal dominant, recessive, and X-linked patterns of inheritance have been demonstrated in families with multiple cases of prostate cancer.14 For these guidelines, the Hopkins criteria52 have been adopted to define familial prostate cancer. Several studies have identified a specific HOXB13 mutation in 1.4–4.6% of individuals (primarily of Northern European ancestry) meeting these criteria.53,54,55 Identifying the basis of familial prostate cancer is ongoing, and genes found to date account for a small portion of families. However, referral may be appropriate for these families to help address concerns and provide screening recommendations.
Referral should be considered for any individual with a personal history of or first-degree relative with (i) three or more first-degree relatives with prostate cancer; (ii) two or more cases of prostate cancer diagnosed before age 55; or (iii) aggressive prostate cancer (Gleason score ≥7) and two or more cases of breast, ovarian, or pancreatic cancer.
Hereditary breast–ovarian cancer syndrome (OMIM 604370 and 612555)
Hereditary breast–ovarian cancer (HBOC) syndrome is caused by mutations in the BRCA1 and BRCA2 genes and is characterized by increased risks for early-onset breast, multiple breast primaries, male breast, and epithelial ovarian, Fallopian tube, or primary peritoneal cancers. In addition, cancers of the pancreas, prostate, and melanoma are more common in individuals with HBOC syndrome. The pathology of “triple-negative phenotype” breast cancer (estrogen receptor–negative, progesterone receptor–negative, and HER2/neu–negative) has been strongly associated with BRCA1 mutations.56,57,58,59 The likelihood of identifying a BRCA1/2 mutation in a woman with ovarian cancer at any age is around 13–18%.60,61,62 Of males with breast cancer, 15–20% have a BRCA1/2 mutation.63 The overall prevalence of BRCA1 mutations is estimated at 1 in 300 and that of BRCA2 mutations is estimated at 1 in 800, but founder mutations in many populations (e.g., Ashkenazi Jewish,64,65,66,67 Icelandic,68 and Mexican Hispanic69 populations) lead to increased mutation prevalence in these populations.
Referral should be considered for any individual with a personal history of or first-degree relative with (i) breast cancer diagnosed at or before age 50; (ii) triple-negative breast cancer diagnosed at or before age 60; (iii) two or more primary breast cancers in the same person; (iv) ovarian, Fallopian tube, or primary peritoneal cancer; (v) Ashkenazi Jewish ancestry and breast or pancreatic cancer at any age; or (vi) male breast cancer. Individuals with a family history of three or more cases of breast, ovarian, pancreatic, and/or aggressive prostate cancer (Gleason score ≥7) (refs. 70,71) should also be referred. Note that this should not include families in which all three cases are aggressive prostate cancer.
Hereditary diffuse gastric cancer (OMIM 137215)
Hereditary diffuse gastric cancer is caused by mutations in the CDH1 gene and is characterized by an increased risk for diffuse gastric cancer, lobular breast cancer, and signet ring colorectal cancer. CDH1 mutations occur in 25–50% of individuals who meet the hereditary diffuse gastric cancer criteria.72 The International Gastric Cancer Linkage Consortium’s most recent consensus guidelines for the clinical management of hereditary diffuse gastric cancer include indications for CDH1 testing and have been adopted below.73
Referral should be considered for any individual with a personal history of or first-degree relative with (i) diffuse gastric cancer diagnosed before age 40; (ii) lobular breast cancer and diffuse gastric cancer in the same person; (iii) lobular breast cancer in one relative and diffuse gastric cancer in another, one diagnosed before age 50; or (iv) two cases of gastric cancer in family, one of which is a confirmed diffuse gastric cancer diagnosed before age 50. Individuals with a family history of three or more relatives with gastric cancer should also be referred.
Hereditary leiomyomatosis and renal cell cancer (OMIM 605839 and 150800)
Hereditary leiomyomatosis and renal cell cancer is caused by mutations in the FH gene and is characterized by increased risks for renal cancer and cutaneous and uterine leiomyomas. Individuals with cutaneous leiomyoma and renal cell tumors of one of three types (papillary type 2 (refs. 74,75,76,77,78)), collecting duct,71,74,75 and tubulopapillary78) should receive genetic counseling referral.79,80 Although studies of the proportion of isolated cases of cutaneous leiomyomas with an FH mutation are not available, 85% of individuals with cutaneous leiomyomas (some of whom were isolated cases and some of whom had a family history of uterine leiomyoma or renal cell tumors) had an FH mutation in several studies.74,75,76,77,81 A FH mutation was found in 17% of patients with papillary type 2 renal cell carcinoma (RCC).
Referral should be considered for any individual with a personal history of or first-degree relative with (i) cutaneous leiomyomas or (ii) RCC with histology characteristic of hereditary leiomyomatosis and renal cell cancer.
Hereditary melanoma, also known as familial atypical mole and malignant melanoma (OMIM 155600)
Hereditary melanoma is caused by mutations in the CDKN2A/ARF gene, which encodes p16 and p14ARF, and the CDK4 gene. Hereditary melanoma is characterized by multiple melanocytic nevi (usually >50) and a family history of melanoma. Individuals with hereditary melanoma have a 17% risk for pancreatic cancer by age 75 (ref. 82). The penetrance for melanoma in families with CDKN2A mutations is at least 28%, although it is perhaps as high as 91% in families with multiple cases.83,84,85 A review of 466 families with at least three cases of melanoma revealed 38% had CDKN2A mutations.86 Penetrance and detection rate vary by geography.84 In addition, 2–3% of these families have mutations in CDK4 (n = 5) and p14ARF (n = 7). CDKN2A gene mutations seem to be rare in families with pancreatic cancer without any cases of melanoma44 but occur in up to 11% (2/18) of families with both pancreatic cancer and melanoma.87
Referral should be considered for any individual with a personal history of or first-degree relative with (i) three or more melanomas in the same person or (ii) three or more cases of melanoma and/or pancreatic cancer.
Hereditary mixed polyposis syndrome (OMIM 201228 and 610069)
Hereditary mixed polyposis syndrome is characterized by multiple polyps of mixed histology (hyperplastic, adenomatous, and juvenile polyps), leading to an increased risk for colorectal cancer. The major gene(s) responsible for hereditary mixed polyposis syndrome have not been identified; however, some cases are caused by mutations in the BMPR1A gene.88,89,90 Also, a founder mutation involving the GREM1 gene was identified in Ashkenazi Jewish patients with hereditary mixed polyposis syndrome.91
Referral should be considered for any individual with a personal history of or first-degree relative with ≥10 colorectal polyps with mixed histology.
Hereditary papillary RCC (OMIM 605074)
Hereditary papillary RCC is caused by mutations in the MET gene and is characterized by an increased risk of developing papillary type 1 RCC. In a series of 129 patients with papillary RCC, 6% (8/129) had a germline MET mutation.92 Because this tumor type is rare, our referral criteria are for anyone with a papillary type 1 RCC. Note that patients with a papillary type 2 RCC should be referred as well because of the possibility of hereditary leiomyomatosis and renal cell cancer.
Referral should be considered for any individual with a personal history of or first-degree relative with a papillary type 1 RCC.
Hereditary paraganglioma–pheochromocytoma syndrome (OMIM 115310, 168000, 605373, 601650, 154950, and 613403)
Hereditary paraganglioma–pheochromocytoma syndrome is caused by mutations in the SDHB, SDHD, SDHC, SDHAF2, MAX, and TMEM127 genes and is characterized by an increased risk for paragangliomas and pheochromocytomas. In multiple series of individuals with paragangliomas and pheochromocytomas, 8–25% had hereditary paraganglioma–pheochromocytoma syndrome due to a germline mutation in the SDHB, SDHC, or SDHD genes.93,94,95,96,97,98 Rates of hereditary paraganglioma–pheochromocytoma syndrome in individuals with a positive family history or other clinical factors (e.g., multiple tumors, head and neck location) are considerably higher.93,94,95,96,97
Referral should be considered for any individual who has a personal history of or a first-degree relative with a paraganglioma or pheochromocytoma.
Hereditary retinoblastoma (OMIM 180200)
Hereditary retinoblastoma is caused by mutations in the RB1 gene and is characterized by a malignant tumor of the retina, usually occurring before age 5. It is estimated that about 40% of all retinoblastomas are hereditary.99 Individuals with a positive family history of retinoblastoma, bilateral tumors, and multifocal tumors have the highest chance to have hereditary retinoblastoma.99 Individuals with hereditary retinoblastoma can also have an increased risk for pinealoblastoma,100 osteosarcomas, sarcoma (especially radiogenic), and melanoma.101,102
Referral should be considered for any individual who has a personal history of or first-degree relative with a retinoblastoma.
Juvenile polyposis syndrome (OMIM 174900)
Juvenile polyposis syndrome is caused by mutations in the SMAD4 (20%) and BMPR1A (20%) genes103 and is characterized by juvenile-type hamartomatous polyps throughout the gastrointestinal (GI) tract. The term juvenile polyp refers to a specific histologic type of polyp, not the age at diagnosis. The risk for GI cancers (mainly colorectal cancer, although cancers of the stomach, upper GI tract, and pancreas have been reported) in families with juvenile polyposis syndrome ranges from 9 to 50%.104 Extraintestinal features such as valvular heart disease (11%), telangiectasia or vascular anomalies (9%, all in SMAD4 carriers), and macrocephaly (11%) can occur.105 Some individuals with juvenile polyposis syndrome due to mutations in the SMAD4 gene may also have symptoms of hereditary hemorrhagic telangiectasia.106,107
Referral should be considered for any individual with a personal history of or first-degree relative with (i) three to five cumulative histologically proven juvenile GI polyps108,109,110; (ii) any number of juvenile GI polyps with a positive family history of juvenile polyposis syndrome; or (iii) multiple juvenile polyps located throughout the GI tract.38,103
Li–Fraumeni syndrome (OMIM 151623)
Li–Fraumeni syndrome (LFS) is caused by mutations in the TP53 gene and is characterized by the core cancers of breast, brain, adrenocortex, and non-Ewing sarcoma,111 with onset often before age 50 and multiple primary tumors.112 Young age at diagnosis (before age 30) and the type of malignancy are good indicators of a TP53 mutation.113 In individuals diagnosed with an adrenocortical tumor or choroid plexus tumor at or before age 18, the likelihood of identifying a TP53 mutation approaches 80 and 100%, respectively.112,114,115 Individuals with a childhood sarcoma have a higher likelihood of LFS; 6.6% had a TP53 mutation in one series (although the majority of these cases would meet the classic LFS criteria).116 For these guidelines, we are adopting a combination of the Eeles and revised Chompret criteria.117 In two large studies, 29%118 and 35%112 of individuals who met the original, slightly more restrictive, Chompret criteria119 had a TP53 mutation. However, 14% of individuals who met the looser Eeles criteria also had a TP53 mutation.112
Referral should be considered for any individual with a personal history of or first-degree relative with (i) two or more close relatives with a tumor in the LFS spectrum ( Table 5 ), one diagnosed at or before age 45; (ii) breast cancer diagnosed before age 30; (iii) two or more LFS tumors in the same person, one diagnosed at or before age 45; (iv) adrenocortical tumor; (v) choroid plexus tumor; or (vi) childhood sarcoma.117
Lynch syndrome (OMIM 120435 and 120436)
Lynch syndrome (LS) is caused by mutations in the following mismatch repair genes: MLH1, MSH2 (including methylation due to an EPCAM deletion), MSH6, or PMS2; LS is characterized by increased lifetime risks for colorectal (40–80%), endometrial (25–60%), ovarian (4–24%), and gastric (1–13%) cancers.120,121 Individuals with LS can also have an increased risk for urothelial carcinoma, glioblastoma, and sebaceous, biliary, small bowel, and pancreatic adenocarcinomas122,123,124,125 ( Table 6 ). The lifetime risks for cancer are lower in individuals with MSH6 and PMS2 mutations.121,125 Most tumors (77–89%) from individuals with LS are characterized by microsatellite instability, which is an expansion or contraction of repetitive areas in the DNA, called microsatellites, due to defective mismatch repair.126 In addition, there are immunohistochemical antibodies available for the four mismatch repair proteins, and one or two of the proteins is absent in 83% of tumors from individuals with LS.126 One or both of these tumor screening tests are sometimes performed at the time of diagnosis for colorectal and endometrial cancer and can serve as an indication for referral for a LS evaluation. The most well-known criteria developed for LS include the Amsterdam criteria and the Bethesda guidelines, both of which have undergone revision.127,128,129,130 Yet neither of these criteria sufficiently considers the breadth of cancers associated with LS. Furthermore, they are complex and difficult to apply. Thus, the criteria selected for this referral guideline are modified from the “Finnish criteria,” which are simple, easy to apply, based on two large population-based studies, and identify the majority of patients found to have LS.124,131,132,133
Referral should be considered for any individual with a personal history of or first-degree relative with (i) colorectal or endometrial cancer diagnosed before age 50; (ii) colorectal or endometrial cancer diagnosed at or after age 50 if there is a first-degree relative with colorectal or endometrial cancer at any age; (iii) synchronous or metachronous colorectal or endometrial cancer; (iv) sebaceous adenoma or carcinoma and one or more additional case of any LS-associated cancer ( Table 6 ) in the same person or in relatives; or (v) a tumor exhibiting mismatch repair deficiency (high microsatellite instability or loss of a mismatch repair protein based on immunohistochemical staining). Individuals with a family history of three or more LS-associated cancers ( Table 6 ) should also be referred.
Melanoma–astrocytoma syndrome (OMIM 155755)
Melanoma–astrocytoma syndrome is caused by mutations involving both CDKN2A and p14ARF, p14ARF alone, and possibly the ANRIL antisense noncoding RNA; it is a rare condition that leads to an increased risk for melanoma and astrocytoma tumors.
Referral should be considered for any individual with a personal history of or first-degree relative with (i) melanoma and astrocytoma in the same person or (ii) one case of melanoma and one case of astrocytoma in two first-degree relatives.
Multiple endocrine neoplasia type I (OMIM 131100)
Multiple endocrine neoplasia type I (MEN1) is caused by mutations in the MEN1 gene and is characterized by increased risk of endocrine and nonendocrine tumors.134 Of individuals with two MEN1 manifestations, 26% had a MEN1 mutation.135 Because of the relatively low mutation detection rates in sporadic cases,134,136,137,138,139 no single MEN1-associated tumor is sufficient to warrant genetic counseling referral, with the exception of gastrinoma, of which 20% are due to MEN1 mutations.140 For this guideline, we are adopting the recommendation of the MEN1 International Consensus134 and the MEN1 Clinical Practice Guidelines.140 Note that this guideline is less stringent than the clinical diagnostic criteria for MEN1.
Referral should be considered for any individual with a personal history of or first-degree relative with (i) two or more different MEN1-associated tumors (adrenal, parathyroid, pituitary, pancreas, or thymic tumor or bronchial carcinoid tumor) in the same person134,141; (ii) gastrinoma134,140; (iii) multiple different pancreatic neuroendocrine tumors in the same person134,140; (iv) parathyroid adenoma diagnosed before age 30 (refs. 140,142); (v) parathyroid adenomas involving multiple glands140,142; or (vi) parathyroid adenoma with family history of hyperparathyroidism or MEN1-associated tumors.142
Multiple endocrine neoplasia type II (OMIM 171400, 155240, and 162300)
Multiple endocrine neoplasia type II (MEN2) is caused by mutations in the RET gene and is characterized by increased risks for medullary thyroid cancer (MTC) (≤100%), pheochromocytomas (≤50%), and parathyroid disease (≤30%).143,144,145 As many as 25% of unselected individuals with MTC have a RET mutation.146 Individual series found that 4–11% of individuals with isolated MTC have a RET mutation.147,148,149 Genetic testing of individuals with nonsyndromic pheochromocytomas detected a RET mutation in 5% of these individuals in one study,150 but lower rates were found in other studies.93,95 RET testing is not indicated in apparently sporadic hyperparathyroidism in the absence of other clinical suspicion for MEN2 (ref. 134). MEN2A accounts for 80% of hereditary MTC syndromes.151 Families with MTC and no other MEN2-associated tumors are referred to as having familial medullary thyroid cancer.143,152 Familial medullary thyroid cancer accounts for 15% of hereditary MTC syndromes.151 MEN2B accounts for 5% of hereditary MTC syndromes and is a more severe type of MEN2, differentiated by the presence of benign oral and submucosal neuromas and a distinct appearance (tall and lanky with an elongated face and large lips).151 Of individuals with MEN2B, 40% have diffuse ganglioneuromatosis of the GI tract. The large majority of patients with MEN2B have mutations in exon 16 (M918T) and, less often, in exon 15 (A883F). There are genotype–phenotype correlations between the specific mutation in RET and the various clinical features.
Referral should be considered for any individual with a personal history of or first-degree relative with (i) MTC; (ii) pheochromocytoma; (iii) oral or ocular neuromas (lips, tongue, sclera, or eyelids); or (iv) diffuse ganglioneuromatosis of the GI tract.
MUTYH-associated polyposis (OMIM 608456)
MUTYH-associated polyposis is a recessive condition caused by biallelic mutations in the MUTYH gene and is characterized by an increased risk for adenomatous colon polyps and colorectal cancer (80%).153 Individuals with MUTYH-associated polyposis can develop only a few adenomatous colon polyps or they can have >100 adenomatous colon polyps.38,154 As a result, this condition can overlap with FAP, attenuated FAP, and LS. Testing is often ordered for both APC and MUTYH at the same time for patients with ≥10 adenomatous colon polyps. MUTYH testing might also be appropriate for patients with colorectal cancer diagnosed before age 50 after LS has been ruled out (the tumor exhibits mismatch repair proficiency), as 0.8–6% have biallelic MUTYH mutations.155,156,157,158 Biallelic MUTYH mutations are found in 2% of patients with ≥1,000 adenomas, 7% of patients with 100–999 adenomas, 7% of patients with 20–99 adenomas, and 4% of patients with 10–19 adenomas.37
Referral should be considered for any individual with a personal history of or first-degree relative with (i) ≥10 cumulative adenomatous colon polyps with or without colorectal cancer or (ii) mismatch repair proficient (microsatellite stable and/or normal mismatch repair protein based on immunohistochemical staining) colorectal cancer diagnosed before age 50.
Nevoid basal cell carcinoma syndrome (OMIM 109400)
Nevoid basal cell carcinoma syndrome is caused by mutations in the PTCH gene and is characterized by the presence of multiple jaw keratocysts beginning in the teens and multiple basal-cell carcinomas beginning in the 20s. Physical features such as macrocephaly, bossing of the forehead, coarse facial features, facial milia, and skeletal anomalies are present in most individuals with nevoid basal cell carcinoma syndrome ( Table 7 ). Less common features include cardiac fibromas (2%), ovarian fibromas (20%), medulloblastoma (primitive neuroectodermal tumor; 5%). The diagnosis is made clinically when an individual has two major diagnostic criteria and one minor diagnostic criterion or one major and three minor diagnostic criteria159,160,161 ( Table 7 ).
Referral should be considered for any individual with a personal history of or first-degree relative with any two criteria from the major or minor diagnostic criteria lists ( Table 7 ).
Peutz–Jeghers syndrome (OMIM 175200)
Peutz–Jeghers syndrome (PJS) is caused by mutations in the STK11 gene and is characterized by mucocutaneous hyperpigmentation of the mouth, lips, nose, eyes, genitalia, or fingers; multiple hamartomatous polyps in the GI tract; and increased risks for colorectal (39% between ages 15 and 64), pancreatic (36%), gastric (29%), and small intestinal (13%) cancers. In addition, there are increased risks for breast cancer (54%), ovarian sex cord tumors with annular tubules (21%), and adenoma malignum of the cervix (10%) and the testes, especially Sertoli cell tumors (9%).162 PJ polyps are hamartomatous with glandular epithelium supported by smooth muscle cells contiguous with the muscularis mucosa.
Referral should be considered for any individual with a personal history of or first-degree relative with (i) two or more histologically confirmed PJ GI polyps; (ii) one or more PJ GI polyp and mucocutanous hyperpigmentation; (iii) ovarian sex cord tumor with annular tubules; (iv) adenoma malignum of the cervix; (v) Sertoli cell tumor; (vi) pancreatic cancer and one or more PJ GI polyp; (vii) breast cancer and one or more PJ GI polyp; or (viii) one or more PJ polyp and a positive family history of PJS.
Rhabdoid tumor predisposition syndrome types I and II (OMIM 609322 and 613325)
Rhabdoid tumor predisposition syndrome is characterized by an increased risk for rhabdoid tumors (rare and aggressive tumors of children). Rhabdoid tumor predisposition syndrome type I is caused by mutations in the SMARCB1 gene. Germline mutations in the SMARCB1 gene occurred in 35% (26/115 and 35/100) of patients with apparently sporadic childhood rhabdoid tumors.163,164 Only 10 of 61 parents harbored the germline mutation in both series combined, indicating a high proportion of germ cell mosaicism or de novo mutations in rhabdoid tumor predisposition syndrome type I.163,164 Rhabdoid tumor predisposition syndrome type II is caused by mutations in the SMARCA4 gene. In two small series of apparently nonfamilial small cell carcinoma of the ovary, hypercalcemic type (which is a rare, aggressive rhabdoid tumor affecting children and young women), germline mutations in SMARCA4 were found in 29% (2/7)165 and 50% (6/12)166 of cases.
Referral should be considered for any individual with a personal history of or first-degree relative with a rhabdoid tumor, including small cell carcinoma of the ovary, hypercalcemic type.
Serrated polyposis syndrome (not in OMIM)
Serrated polyposis syndrome is a syndrome characterized by serrated polyps (SPs) and an increased risk for colorectal cancer. SPs can be difficult to diagnose and include hyperplastic polyps, sessile SPs, or adenomas, as well as traditional serrated adenomas. For these guidelines we adopt the 2012 National Comprehensive Cancer Network modification (http://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf) of the 2000 World Health Organization criteria167 for the diagnosis of serrated polyposis syndrome. No causative mutations in BMPR1A, SMAD4, PTEN, MUTYH, or GREM1 were found in a series of 65 individuals with serrated polyposis syndrome; it is likely that this condition is caused by novel genes that have yet to be discovered.168 Although genetic testing may not be useful at present, a genetics referral is indicated because the diagnosis will affect future management, and other polyposis syndromes should be ruled out.
Referral should be considered for any individual with a personal history of or first-degree relative with (i) at least 5 SPs proximal to the sigmoid colon, 2 of which are >1 cm in diameter, (ii) >20 SPs throughout the large bowel,38,169 or (iii) any number of SPs proximal to the sigmoid colon and a positive family history of serrated polyposis syndrome.
Tuberous sclerosis complex (OMIM 191100)
Tuberous sclerosis complex (TSC) is caused by mutations in the TSC1 and TSC2 genes and is characterized by brain, kidney, and heart tumors, as well as skin and neurological abnormalities, among others170,171 ( Table 8 ). Brain lesions in TSC are complex and include subependymal nodules, cortical hamartomas, areas of focal cortical hypoplasia, and heterotopic gray matter.171,172 When cerebral cortical dysplasia and cerebral white matter migration lines occur together, they should be counted as one rather than two features of TSC.170,171 Renal lesions (angiomyolipomas and/or cysts) are usually present during childhood, and prevalence increases with age.171 About two-thirds of newborns with TSC have one or more cardiac rhabdomyomas; they are largest during the neonatal period and regress with time.173 Skin lesions occur in nearly 100% of individuals, although none are pathognomonic.170 Retinal lesions are present in 87% of individuals with TSC but may be difficult to detect without dilating the pupils and using indirect ophthalmoscopy.171,174 Interestingly, two-thirds to three-fourths of individuals with TSC have de novo mutations.171 Clinical diagnostic criteria involve combinations of major and minor criteria170,171 ( Table 8 ). We recommend referral for anyone meeting any two criteria from the major or minor diagnostic criteria lists.
Referral should be considered for any individual with a personal history of or first-degree relative with any two criteria from the major or minor diagnostic criteria lists in the same person170,171 ( Table 8 ).
Von Hippel–Lindau syndrome (OMIM 193300)
Von Hippel–Lindau syndrome is caused by mutations in the VHL gene and is characterized by RCC (clear cell histology), hemangioblastomas, pheochromocytomas, and endolymphatic sac tumors. Simplex cases of central nervous system hemangioblastoma, pheochromocytoma, and endolymphatic sac tumor are each sufficient to warrant genetic counseling referral. VHL mutations are detected in 10–40% of individuals with isolated central nervous system hemangioblastoma,175 46% of those with isolated retinal capillary hemangioma,176 3–11% of those with isolated pheochromocytoma,93,95,96,150,175,177,178 and about 20% of those with an endolymphatic sac tumor.179,180,181,182,183 Single cases of unilateral, unifocal RCC diagnosed at or after age 50 are insufficient to warrant referral to genetic counseling.175,184
Referral should be considered for any individual with a personal history of or first-degree relative with (i) clear cell RCC if he or she (a) has bilateral or multifocal tumors, (b) is diagnosed before age 50, or (c) has a close relative with clear cell RCC; (ii) central nervous system hemangioblastoma; (iii) pheochromocytoma; (iv) endolymphatic sac tumor, or (v) retinal capillary hemangioma.
This document suggests referral guidelines for 28 of the most common hereditary cancer susceptibility syndromes. The tables are meant to aid busy clinicians, enabling them to quickly search by cancer type ( Table 1 includes common cancers, Table 2 includes rare benign and malignant tumors) to find appropriate referral criteria for the various syndromes detailed throughout this guideline. After locating the cancer of interest in the table, practitioners can learn more about the associated syndrome by looking it up in the text of this document. We recommend that patients (or their affected relatives) meeting any of the cancer genetics referral criteria be referred to a cancer genetics specialist. To find a cancer genetics expert, visit the National Cancer Institute Cancer Genetics Services Directory (http://www.cancer.gov/cancertopics/genetics/directory), the National Society of Genetic Counselors website (http://www.nsgc.org; use the “Find a Genetic Counselor” feature), or the American College of Genetics and Genomics website (http://www.acmg.net; use the “Find Genetic Services” feature).
H.H. has received grant support from Myriad Genetic Laboratories in the form of donated genetic testing she has received honoraria for speaking from Quest Diagnostics, InVitae Genetics, and Myriad Genetic Laboratories in the past 3 years. This has not impacted the referral guidelines. A.B. has received National Institutes of Health funding but reports that it does not conflict with the content of this practice guideline. R.P. has received grant support from Myriad Genetic Laboratories in the form of donated genetic testing G.W. was supported by institutional funds from the Vanderbilt University School of Medicine. A.B., G.W., and R.L.B. declare no conflict of interest.
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Document approved by the ACMG Board of Directors 31 July 2014. Document approved by the NSGC Board of Directors 25 August 2014.
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Hampel, H., Bennett, R., Buchanan, A. et al. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med 17, 70–87 (2015). https://doi.org/10.1038/gim.2014.147
- cancer genetics
- cancer predisposition
- genetic counseling
- referral guidelines
- referral indications
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