Cigna Genetic Testing for Hereditary Cancer Susceptibility Syndromes - (0518) Form

Genetics Genetic Testing Collateral File Transvaginal Ultrasound, Non-Obstetrical

This Coverage Policy addresses genetic testing for germline pathogenic or likely pathogenic variants related to hereditary cancer susceptibility syndromes. Germline variants are inherited; that is, passed down in families by blood relatives. Types of testing include single-site testing, full sequence analysis, duplication/deletion analysis or multi-gene panel testing. Genetic counseling is required prior to genetic testing for germline pathogenic or likely pathogenic variants related to all hereditary cancer susceptibility syndromes to educate and promote informed choices regarding testing options.

Coverage Policy

Some benefit plans limit coverage of genetic testing and genetic counseling services. Please refer to the applicable benefit plan language to determine benefit availability and terms, conditions and limitations of coverage for the services discussed in this Coverage Policy. Genetic counseling is required prior to and after genetic testing for ALL hereditary cancer susceptibility syndromes as outlined in this Coverage Policy. Please refer to the following criteria for additional information regarding coverage for genetic counseling and genetic testing.

For additional information regarding coverage for specific genetic tests please refer to the Genetic Testing Collateral File.

Medical Coverage Policy: 0518

General Criteria for Germline Pathogenic or Likely Pathogenic Variant Genetic Testing:

Hereditary Cancer Susceptibility/Risk Assessment

Medically Necessary

Syndrome/hereditary condition specific genetic testing for hereditary cancer susceptibility is considered medically necessary when ALL of the following criteria are met:

• gene testing results will impact medical management
• there are National Comprehensive Cancer Network™(NCCN Guidelines™) category 1, 2A or 2B guidelines and/or other published evidence-based management recommendations for an individual who tests positive for the condition/syndrome-specific gene(s) for which testing is being requested
• the individual being tested is the most appropriate person to test or the most appropriate family member is unavailable for testing

EITHER of the following personal and/or family history is consistent with the hereditary cancer syndrome being tested for when the syndrome is not specifically addressed in this policy:

1. a recommendation for testing is confirmed by ONE of the following:
• an independent Board-Certified or Board-Eligible Medical Geneticist
• an American Board of Medical Genetics or American Board of Genetic Counseling-certified Genetic Counselor not employed by a commercial genetic testing laboratory (Genetic counselors are not excluded if they are employed by or contracted with a laboratory that is part of an Integrated Health System which routinely delivers health care services beyond just the laboratory test itself).
• a genetic nurse credentialed as either a Genetic Clinical Nurse (GCN) or an Advanced Practice Nurse in Genetics (APGN) by either the Genetic Nursing Credentialing Commission (GNCC) or the American Nurses Credentialing Center (ANCC) who is not employed by a commercial genetic testing laboratory (Genetic nurses are not excluded if they are employed by or contracted with a laboratory that is part of an Integrated Health System which routinely delivers health care services beyond just the laboratory test itself).

• a treating breast surgeon, who has determined that the results of testing will influence surgical decision making in an individual recently diagnosed with early stage breast cancer who:
1. has evaluated the individual
2. completed a three-generation pedigree
3. intends to engage in post-test follow-up counseling or, if a breast surgeon treating a patient with recently diagnosed breast cancer, intends to refer to an appropriately credentialed independent genetic counselor for post-test counseling

Germline Testing Following Identification of a Somatic Pathogenic or Likely Pathogenic Variant

Medically Necessary

Germline testing, after a somatic variant is identified through the evaluation of solid or hematologic malignancy, is considered medically necessary when ALL of the following criteria are met:

• there are NCCN Guidelines category 1, 2A or 2B and/or other published management recommendations specific to the variant identified
• the variant identified has a high rate of germline incidence based on gene and tumor type and/or family history (e.g., BRCA1 in any tumor type, TP53 in adenoid cystic carcinoma diagnosed in a child)

Germline Pathogenic or Likely Pathogenic Variant Genetic Testing for Hereditary Cancer Susceptibility Syndromes

Medically Necessary

Genetic testing is considered medically necessary when the individual meets the general criteria for hereditary cancer genetic testing as above AND current National Comprehensive Cancer Network™ (NCCN Guidelines™) category 1, 2A or 2B guidelines for the testing requested for ANY of the following hereditary cancer susceptibility syndromes (see NCCN Guidelines™ for associated gene(s)):

• Genetic/Familial High-Risk Assessment: Colorectal (e.g., Lynch syndrome** genes, FAP/MUTYH and other polyposis syndromes)
• Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic (including prostate cancer, Cowden syndrome/PTEN hamartoma tumor syndrome and Li Fraumeni syndrome)
• Prostate Cancer
• Neuroendocrine and Adrenal Tumors (e.g., MEN1, MEN2, VHL, PGL/PCC)
• Gastric Cancer (e.g., Diffuse gastric cancer)
• Melanoma: Cutaneous
• Myelodysplastic Syndromes
• Acute Myeloid Leukemia

** Lynch syndrome related-cancers for criteria evaluation are: colorectal, endometrial, keratoacanthoma, stomach, ovarian, small bowel, ureter or renal pelvis, sebaceous adenoma or carcinoma, hepatobiliary, pancreas, brain cancer. When appropriate tumor is available and a familial pathogenic or likely pathogenic variant is not known, Lynch syndrome tumor analysis should be performed prior to germline testing. Lynch syndrome somatic variant analysis is discussed in Cigna Coverage Policy: Molecular Diagnostic Testing for Hematology and Oncology Indications.

Retinoblastoma-RB1

Medically Necessary

Genetic testing for retinoblastoma (RB1 gene) is considered medically necessary when an individual meets general criteria for hereditary cancer genetic testing as noted above for EITHER of the following indications:

• germline DNA testing (e.g., peripheral blood, saliva) for ANY of the following:
• at-risk individual from a family with a pathogenic or likely pathogenic variant RB1 gene
• bilateral retinoblastoma
• unilateral retinoblastoma with ONE of the following:
• pathogenic or likely pathogenic variant(s) identified in tumor tissue
• multifocal retinoblastoma
• first-, second-, and third-degree relative*** with history of retinoblastoma
• tumor tissue is not available
• testing of retinoblastoma tumor tissue for EITHER of the following:
• unilateral retinoblastoma and no first-, second-, and third-degree blood relative*** with a history of retinoblastoma
• bilateral retinoblastoma with BOTH of the following:
• no family history of retinoblastoma
• a pathogenic or likely pathogenic variant has not been detected in the blood

***A first-degree relative is defined as a blood relative with whom an individual shares approximately 50% of his/her genes, including the individual's parents, full siblings, and children. A second-degree relative is defined as a blood relative with whom an individual shares approximately 25% of his/her genes, including the individual's grandparents, grandchildren, aunts, uncles, nephews, nieces, and half-siblings. A third-degree relative is defined as a blood relative with whom an individual shares approximately 12.5% of his/her genes, including the individual’s great-grandparents and first- cousins.

Genetic testing for retinoblastoma is considered medically necessary using ANY of the following genetic testing methods when DNA sequence and deletion/duplication analysis is negative and clinical suspicion of a pathogenic or likely pathogenic variant in the RB1 gene remains high:

• methylation analysis (tumor)
• sequence analysis of RNA (blood)

von Hippel-Lindau Syndrome-VHL

Medically Necessary

Genetic testing is considered medically necessary for von Hippel-Lindau (VHL) syndrome when individual meets general criteria for hereditary cancer genetic testing as noted above and ANY of the following indications:

• At risk individual from a family with a pathogenic or likely pathogenic variant VHL gene
• Retinal angioma/hemangioblastoma
• Spinal or cerebellar hemangioblastoma
• Adrenal or extra-adrenal pheochromocytoma
• Renal cell carcinoma, if the patient is < age 47 years or has a personal or family history of any other tumor typical of VHL
• Multiple renal and pancreatic cysts
• Neuroendocrine tumors of the pancreas
• Endolymphatic sac tumors
• Multiple papillary cystadenomas of the epididymis or broad ligament

Not Medically Necessary

Genetic testing for hereditary cancer susceptibility syndromes is considered not medically necessary if the above criteria are not met.

Genetic testing for hereditary cancer susceptibility for screening in the general population is considered not medically necessary.

General Background

Hereditary cancer syndromes are a heterogeneous group of disorders; the presence of one or a combination of gene variants may increase the risk for development of specific cancers.

Germline variants are inherited; that is, passed down in families by blood relatives. For example, Lynch syndrome may increase the risk for colorectal, endometrial, gastric, ovarian and small bowel cancer. Other hereditary cancer syndromes include hereditary breast and ovarian cancer, retinoblastoma, von Hippel-Lindau, multiple endocrine neoplasia type 1 (MEN1), type 2A and 2B and RET, hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndrome, Peutz-Jeghers syndrome, hereditary diffuse gastric cancer and prostate cancer. Variations in the CHEK2 and PALB2 genes have also been implicated for an increased risk for hereditary breast cancer.

Support for germline pathogenic or likely pathogenic variant testing and genetic counseling for hereditary cancer syndromes is available in the form of published evidence-based management recommendations and evidence in the published, peer-reviewed scientific literature.

Genetic Counseling

Genetic counseling is defined as the process of helping an individual understand and adapt to the medical, psychological and familial indications of genetic contributions to disease. Genetic counseling services span the life cycle from preconception counseling to infertility evaluation, prenatal genetic screening and diagnosis, and include predisposition evaluation and genetic diagnosis (National Society of Genetic Counselors [NSGC], 2021; Edwards, 2010).

A variety of genetics professionals provide these services: Board-Certified or Board-Eligible Medical Geneticists, an American Board of Medical Genetics or American Board of Genetic Counseling-certified Genetic Counselor, and genetic nurses credentialed as either a Genetic Clinical Nurse (GCN) or an Advanced Practice Nurse in Genetics (APGN) by either the Genetic Nursing Credentialing Commission (GNCC) or the American Nurses Credentialing Center (ANCC). Individuals should not be employed by a commercial genetic testing laboratory, although counseling services by these individuals are not excluded if they are employed by or contracted with a laboratory that is part of an Integrated Health System which routinely delivers health care services beyond just the laboratory test itself.

Pre- and post- test genetic test counseling is required for ALL hereditary cancer susceptibility syndromes to interpret family and medical histories and assess the chance of disease occurrence and recurrence, educate regarding inheritance, testing, management prevention and resources, and counsel to promote informed choices and adaptation to risk or condition.

Medical Coverage Policy: 0518 General Criteria for Germline Pathogenic or Likely Pathogenic Variant Testing for Hereditary Cancer Susceptibility/Risk Assessment

Germline variants are inherited; that is, passed down in families by blood relatives. The goal of germline pathogenic or likely pathogenic variant genetic testing is to identify variants that may be passed down in families by blood relatives. As described in this Coverage Policy, genetic testing may be appropriate when the individual for which testing is being considered meets the genetic testing criteria and is recommended by an appropriately credentialed genetics professional, or in an individual with early stage breast cancer, when the treating breast surgeon determines that the results of genetic testing will influence surgical management and intends to refer the individual to an appropriately credentialed independent genetic counselor for follow-up counseling. Germline testing for hereditary cancer susceptibility syndromes is supported by a number of published evidence-based recommendations, including consensus guidelines by the National Comprehensive Cancer Network™ (NCCN) (NCCN Guidelines™).

The NCCN has published Category 1, 2A and 2B recommendations for this testing as an important component in the assessment and management of several hereditary cancer susceptibility syndromes. These include Lynch syndrome, familial adenomatous polyposis/attenuated familial adenomatous polyposis, MYH-associated polyposis, hereditary breast and ovarian cancer syndrome, juvenile polyposis syndrome, Peutz-Jeghers, Cowden and Li Fraumeni syndrome, multiple endocrine neoplasia types 1 and 2, and diffuse gastric cancer. Detailed information regarding these recommendations can be found on the NCCN website at https://www.nccn.org. Germline variant testing for adult onset diseases in at-risk children <18 years is generally not recommended. Testing for hereditary cancer syndromes in children <18 who do not have a phenotype for the disorder (i.e., are asymptomatic) is only indicated when the related risks and management guidelines impact individuals prior to age 18. There is insufficient evidence in the published, peer-reviewed medical literature to demonstrate improved health outcomes for general population screening for hereditary cancer susceptibility. Testing methodology, targeting DNA and/or RNA, has been clinically validated and is the most accurate method unless technical limitations (e.g. poor sample quality) necessitate the need for alternate testing strategies.

Professional Society/Organization

For a summary of professional society recommendations/guidelines regarding germline pathogenic or likely pathogenic variant genetic testing for hereditary cancer susceptibility syndromes, please click here.

Germline Testing Following Identification of a Somatic Pathogenic or Likely Pathogenic Variant

As tumor testing, especially broad molecular profiling becomes more common, it is expected that there will be an increase in the number of somatic variants identified in genes associated with hereditary cancer syndromes. In most cases, this is associated with a risk that a germline pathogenic or likely pathogenic variant will be identified, but with certain cancer types and genes, the likelihood of an underlying germline variant remains low. In addition, many types of tumors have a high rate of variation in genes associated with hereditary cancer syndromes, but unrelated to the same tumor type. An often cited example of this is the high-rate of APC variants identified in endometrial cancer, despite the fact that germline variations in APC are not associated with an increased risk of endometrial cancer.

Several studies have shown that the prevalence of pathogenic germline variants among those in whom somatic variants have been identified is high enough to consider germline testing in most actionable genes (Schrader, et al., 2016; Catenacci, et al., 2015). One of the largest studies to date, using a broad molecular profiling platform, predicted that variations in high-risk cancer genes were likely pathogenic or pathogenic in 3.1 to 7% of tumor samples tested; however, the study design did not compare the tumor DNA to normal. Additionally, this study noted the rate of germline variants varies widely by tissue type and gene (Hall, et al., 2015). It has been noted that identification of TP53, STK11, PTEN and APC in tumor tissue are less likely to be associated with germline variations (Jain, et al., 2016). For instance, TP53 variants are identified in almost 85% of ovarian tumors (COSMIC data), but fewer than 3% of patients with apparently hereditary ovarian cancer syndromes will test positive for a TP53 variant.

Therefore, additional factors, such as clinical presentation, family history, or data obtained from variant databases regarding likelihood of a germline origin should be considered when determining medical necessity of germline testing for these actionable genes.

Germline Genetic Testing for Hereditary Cancer Susceptibility Syndromes

Genetic/Familial High-Risk Assessment: Colorectal (e.g., Lynch syndrome genes, FAP/MUTYH and other polyposis syndromes)

Lynch syndrome (LS) is the most common type of hereditary colorectal cancer, accounting for 20–35% of all inherited forms. Disease-specific criteria for genetic testing for Lynch syndrome-associated cancers, familial adenomatous polyposis/attenuated familial adenomatous polyposis, juvenile polyposis and MYH- associated polyposis have been established by professional consensus guidelines, including those published by the NCCN and include timeframes and methods for surveillance and recommendations for testing when there is a personal and/or family history of these hereditary cancer syndromes.

LS-related cancers include colorectal, endometrial, keratocanthoma, stomach, ovarian, small bowel, ureter or renal pelvis cancers as well as sebaceous adenoma or carcinoma, hepatobiliary, pancreas and brain cancer. Several clinical prediction models exist to determine an individual's risk for LS. These computer programs give probabilities of variants and/or of the development of future cancers based on family and personal history.

In general, genetic testing for LS is not recommended for at-risk individuals under the age of 18. However, it is recommended that cancer screening begin two to five years before the earliest age of cancer onset in the family. Therefore, in some situations, screening may need to begin before the age of 18 years (Idos and Valle, 2004).

Professional Society/Organization

For a summary of professional society recommendations/guidelines regarding colorectal cancer (e.g., Lynch syndrome genes, FAP/MUTYH and other polyposis syndromes), please click here.

Genetic/Familial High-Risk Assessment: Breast, Ovarian and Pancreatic (including prostate cancer, Cowden syndrome/PTEN hamartoma tumor syndrome and Li Fraumeni syndrome)

While the vast majority of breast cancer cases do not demonstrate strong familial tendencies, it has been reported that 5–10% are due to inherited forms of the disease, with similar rates reported for ovarian cancer (National Cancer Institute [NCI], 2017). Several genes associated with the predisposition to breast and ovarian cancers have been identified.

Specific genetic variants found in two autosomal dominant cancer predisposition genes, BReast CAncer Susceptibility 1 (BRCA1) and BReast CAncer Susceptibility 2 (BRCA2) are thought to account for the majority of inherited forms of breast and ovarian cancers through an autosomal dominant inheritance pattern for predisposition. The risk of developing cancer depends on numerous variables, including the penetrance of the variant, the biological sex and the age of the individual.

The goal of BRCA1 and BRCA2 testing is to provide patients and their physicians with information that will allow them to make informed decisions regarding cancer prevention, screening, surveillance, and treatment options (e.g., prophylactic surgery). A significant benefit of genetic testing is the ability to quantify cancer risk estimates more precisely, thereby improving the process of determining the most appropriate management strategies in patients who test positive. For patients who test negative, unnecessary treatment (e.g., prophylactic surgery) may be avoided.

Disease-specific Criteria for Hereditary Breast and Ovarian Cancer Syndrome

Disease-specific criteria for genetic testing for hereditary breast and ovarian cancer syndrome have been established by published evidence-based recommendations, including those distributed by the NCCN. There is sufficient evidence in the published, peer-reviewed scientific literature to demonstrate that testing methods used to identify BRCA variants are accurate in detecting specific variations. Sensitivity of BRCA testing has been reported to identify up to 98% of all variants, and sequencing should detect almost 100% of all nucleotide differences. The specificity of BRCA testing has not been well studied.

Cowden Syndrome

Cowden syndrome is a disorder characterized by multiple noncancerous, tumor-like growths called hamartomas and an increased risk of developing certain cancers. Cowden syndrome is inherited in an autosomal dominant pattern. Other cases may result from new mutations in the gene (MedlinePlus, 2021).

Li Fraumeni Syndrome

Li Fraumeni syndrome is a very rare hereditary cancer syndrome predisposing an individual to an increased risk for breast cancer, osteosarcoma and cancers of the soft tissues, particularly in children and young adults. Other cancers commonly seen in this syndrome include brain tumors, leukemias, and adrenocortical carcinoma. This disorder is related to germline variations in the TP53 gene (MedlinePlus, 2021). Li-Fraumeni syndrome is inherited in an autosomal dominant pattern. Genetic testing criteria are estimated to have a high positive predictive value and high specificity, but low sensitivity.

Professional Society/Organization

For a summary of professional society recommendations/guidelines regarding genetic testing for susceptibility to breast, ovarian and pancreatic cancer (including prostate cancer, Cowden syndrome/PTEN hamartoma tumor syndrome and Li Fraumeni syndrome), please click here.

Prostate Cancer

Recommendations for germline genetic pathogenic or likely pathogenic variant testing are based on recommendations from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guideline®) for Prostate Cancer (2021). Germline genetic testing should be considered for an individual with early stage, non-metastatic cancer when there is a strong family history of hereditary cancer. Germline genetic variant testing (i.e., MLH1, MSH2, MSH6, PMS2, BRCA 1, BRCA2, ATM PALB2, CHEK2, and RAD51D) is recommended for an individual with localized stage III (i.e., NCCN® high-risk and very high-risk group), regional or metastatic prostate cancer to assist with genetic counseling, decisions regarding early use of platinum chemotherapy or eligibility for clinical trials, such as those for Poly (ADP-ribose) polymerase (PARP) inhibitors.

Neuroendocrine and Adrenal Tumors (e.g., MEN1, MEN2, VHL, PGL/PCC)

Medical Coverage Policy: 0518 Multiple endocrine neoplasia (MEN) is a group of disorders that affect the endocrine system. Multiple endocrine neoplasia involves tumors (neoplasia) in at least two endocrine glands which can be benign or cancerous. If the tumors are cancerous they can be life-threatening. Type 1 frequently involves tumors of the parathyroid glands, the pituitary gland, and the pancreas. Type 2 is a form of thyroid cancer called medullary thyroid carcinoma; an adrenal gland tumor called a pheochromocytoma, develops in some individuals with resulting elevated blood pressure. Hereditary paraganglioma-pheochromocytoma is a condition characterized by the growth of noncancerous (benign) tumors in groups of cells that are found near nerve cell bunches. A type of paraganglioma known as a pheochromocytoma develops in the adrenal glands. Several genes have been identified as causative in this syndrome, including SDHD (type 1), SDHAF2 (type 2), SDHC (type 3) and SDHB (type 4). Inheritance is in an autosomal dominant pattern.

Gene variants lead to the loss or reduction of SDH enzyme activity (MedlinePlus, 2021).

Professional Society/Organization

For a summary of professional society recommendations/guidelines regarding genetic testing for neuroendocrine and adrenal tumors, please click here.

Gastric Cancer (e.g., Diffuse gastric cancer)

Diffuse gastric cancer (DGC) is a hereditary cancer syndrome that is transmitted in an autosomal dominant pattern. It is characterized by the development of diffuse (signet ring) cancers. More than 120 inherited variations in the CDH1 gene have been identified. Individuals with the CDH1 gene variants associated with hereditary DGC have an approximately 80 percent chance of developing gastric cancer in their lifetimes. Women with these variants also have a 40 to 50 percent chance of developing lobular breast cancer (National Institutes of Health [NIH], 2021).

Melanoma: Cutaneous

Cutaneous melanoma is a type of skin cancer that originates in pigment-producing cells called melanocytes. Development of melanoma can occur from already existing moles and skin growths, or new growths. In most cases, the genetic changes occur throughout a person’s lifetime and can only be detected in the melanocytes. Around ten percent of cases are familial cases caused by inherited germline mutations including genes CDKN2A and MC1R (NIH, 2021).

Myelodysplastic Syndromes

Myelodysplastic syndromes (MDS) are bone marrow disorders in which the bone marrow does not make enough healthy blood cells from stem cells housed in the bone marrow. In MDS, some of the stem cells are abnormal interfering with the development into normal cells. This causes a crowding out of the normal cells in the bone marrow. The World Health Organization recognizes six main types of MDS: MDS with single lineage dysplasia (MDS-SLD); MDS with ring sideroblasts (MDS-RS); MDS with multilineage dysplasia (MDS-MLD); MDS with excess blasts; MDS, unclassifiable (MDS-U); MDS with isolated del(5q). Approximately 50% of patients have a detectable cytogenetic abnormality, most commonly a deletion of all or part of chromosome 5 or 7, or trisomy 8. MDS with isolated del(5q) is associated with an isolated del(5q) cytogenetic abnormality (NCI, 2022).

Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a type of blood cancer that starts in the blood stem cells of bone marrow. Through the maturing process to form blood cells, blood stem cells first mature into either myeloid progenitor cells or lymphoid progenitor cells. Myeloid progenitor cells further mature into myeloblasts (that further mature into granulocytes [a type of white blood cell]), red blood cells, or platelets. AML affects myeloid progenitor cells stopping myeloblasts from becoming mature blood cells. This results in a buildup of myeloblasts in the marrow and blood, and not enough red blood cells, platelets and mature granulocytes (NCCN, 2022). Approximately 50% of patients with AML have detectable chromosomal abnormalities making cytogenetic analysis effective in the evaluation of suspected AML (NCI, 2022).

Retinoblastoma (RB1)

Retinoblastoma occurs in heritable (25%–30%) and nonheritable or sporadic (70%–75%) forms and primarily occurs before the age of five years (NCI, 2021). Germline retinoblastoma is associated with a gene variant that occurs in all of the body's cells. With the germline form of the disease there is an increased risk of developing other cancers such as pinealoma, osteosarcoma and melanoma. Germline disease includes those patients with a positive family history (e.g., hereditary disease) and those patients who have sustained a new germline variant at the time of conception. The gene variant is transferred in an autosomal dominant pattern.

Genetic testing may assist in identifying individuals with a germline variant.

Professional Society/Organization

For a summary of professional society recommendations/guidelines regarding genetic testing for retinoblastoma, please click here.

von Hippel-Lindau Syndrome (VHL)

von Hippel-Lindau (VHL) disease or syndrome is an autosomally dominant inherited multisystem disorder characterized by abnormal growth of blood vessels. VHL is characterized by hemangioblastomas of the brain, spinal cord and retinas; clear cell renal cell carcinomas; pheochromocytomas; endolymphatic sac tumors of the middle ear, serous cystadenoma, neuroendocrine tumors of pancreas and papillary cytadenoma of the epididymis. Tumors may be cancerous or benign; however, even if noncancerous they may be life-threatening. Unlike most autosomal dominant conditions, in which one altered copy of a gene in each cell is sufficient to cause the disorder, two copies of the VHL gene must be altered to trigger tumor and cyst formation. The majority of individuals with one VHL variant will acquire a second altered gene during their lifetime (NIH, 2021). It is estimated that 80% of individuals with VHL syndrome have an affected parent, and approximately 20% have VHL syndrome as the result of a de novo gene mutation. Mutations of the VHL gene have a high penetrance with almost all individuals with a variant exhibiting disease-related symptoms by age 65 years (van Leeuwaarde, et al., 2020).

Molecular genetic testing of the VHL gene detects variation in nearly 100% of affected individuals with suspected or known VHL. For individuals with manifestations of VHL syndrome who do not meet strict diagnostic criteria and who do not have a detectable VHL germline variant, somatic mosaicism for a de novo VHL disease-causing variant should be considered (Sgambati, et al., 2000). Because early detection of at-risk individuals affects medical management, testing of individuals during childhood who have no symptoms is beneficial (American Society of Clinical Oncology [ASCO], 2003). Since ophthalmological screening for those at risk for VHL begins before age five, molecular genetic testing may be considered in young children if the results would alter the medical management.

Single Nucleotide Polymorphisms (SNPs)

Unlike high-penetrance cancer susceptibility gene variants (e.g. BRCA1/2), cancer single nucleotide polymorphisms (SNPs) convey smaller risks for a much larger number of people. SNPs may be characterized as low to moderate penetrant gene variants and involve prediction of an individual’s risk for disease based on genetic polymorphisms common in the population. Until their individual and collective influences on cancer risk are evaluated prospectively, they are not considered clinically relevant (NCI, 2021).

Clinical validity and clinical utility of cancer risk predictive SNP testing is unknown. Whether SNP testing can lead to biologically useful information is under debate. Controlled clinical trial data regarding SNP testing demonstrating improved health outcomes are lacking in the published peer-reviewed scientific literature. Unlike guidelines and criteria that have been established for BRCA testing, criteria have yet to be defined for requirements for when genetic testing of candidate genes or SNPs should be implemented in routine diagnostics (Ripperger, et al., 2009). At this time the role of SNP testing has not been established for the diagnosis or management of hereditary cancer syndromes.

Use Outside of the US

For a summary of professional society recommendations/guidelines regarding genetic testing, please click here.

Medical Coverage Policy: 0518