Code Description
CPT 81404 Molecular pathology procedure, Level 5 (eg, analysis of 2 - 5 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 6 -10 exons, or characterization of a dynamic mutation disorder/triplet repeat by Southern blot analysis)
0009M Fetal aneuploidy (trisomy 21 and 18) DNA sequence analysis of selected regions using maternal plasma, algorithm reported as a risk score for each trisomy
81420 Fetal chromosomal aneuploidy (eg, trisomy 21, monosomy X) genomic sequence analysis panel, circulating cell-free fetal DNA in maternal blood, must include analysis of chromosomes 13, 18 and 21
81422 Fetal chromosomal microdeletion(s) genomic sequence analysis (eg, DiGeorge syndrome, Cri-du-chat syndrome), circulating cell-free fetal DNA in maternal blood
81479 Unlisted molecular pathology procedure
81507 Fetal aneuploidy (trisomy 21, 18, and 13) DNA sequence analysis of selected regions using maternal plasma, algorithm reported as a risk score for each trisomy
81599 Unlisted chemistry procedure
84999 Unlisted chemistry procedure
Introduction
Melanoma is one type of skin cancer. It begins in the melanocyte cells of the skin. These cells produce a pigment(melanin) that gives the skin its color, all the way from pink to dark. Damage to the DNA in melanocytes can cause the cells to grow out of control, leading to melanoma. It’s believed the main cause of melanoma is too much exposure to ultraviolet light, such as getting bad sunburns or using tanning lamps. Another risk factor is family history.If one person has melanoma then there’s a greater chance that the parent, child, brother, or sister could also develop melanoma.For those at high risk of getting melanoma , medical experts say the best ways to reduce the risk are to limit sun exposure, use sunscreen, and watch for unusual moles or other unusually colored areas of the skin. Genetic tests have been created to look for genetic changes related to melanoma. But results from these genetic tests wouldn’t change recommendations for high risk people. Medical studies don’t show how genetic testing will lead to better health results. Genetic testing for melanoma is considered unproven .
Note:
The Introduction section is for your general knowledge and is not to be taken as policy coverage criteria. The rest of the policy uses specific words and concepts familiar to medical professionals. It is intended for providers.A provider can be a person, such as a doctor, nurse, psychologist, or dentist. A provider also can be a place where medical care is given, like a hospital, clinic,or lab.This policy informs them about when a service may be covered.
Genetics Nomenclature Update
The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics (see Table 1). The Society’s nomenclature is recommended by the Human Variome Project, the Human Genome Organization, and by the Human Genome Variation Society itself.
The American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table 2 shows the recommended standard terminology—“pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign”—to describe variants identified that cause Mendelian disorders
Genetic Counseling
Experts recommend formal genetic counseling for patients who are at risk for inherited disorders and who wish to undergo genetic testing. Interpreting the results of genetic tests and understanding risk factors can be difficult for some patients; genetic counseling helps individuals understand the impact of genetic testing, including the possible effects the test results could have on the individual or their family members. It should be noted that genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing; further, genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.
Benefit Application
Genetic testing for genes associated with cutaneous malignant melanoma will likely be performed at specialty laboratories.
Description
Cutaneous melanoma is the third most common type of skin cancer, but the most lethal. Some cases of cutaneous malignant melanoma are familial. Potential genetic markers for this disease are being evaluated in affected individuals with a family history of disease and in unaffected individuals in a high -risk family
Cutaneous Malignant Melanoma
A genetic predisposition to Cutaneous Malignant Melanoma (CMM)is suspected in these specific clinical situations:
*Melanoma has been diagnosed in multiple family members
*Multiple primary melanomas are identified in a single patient
*Melanomas began at an early age
A positive family history of melanoma is the most significant risk factor. It is estimated that approximately 10% of patients with melanoma have a first -or second -degree relative with melanoma. Although some of the familial risk may be related to shared environmental factors, 3 main genes involved in CMM susceptibility have been identified. Cyclin-dependent kinase inhibitor 2A (CDKN2A), located on chromosome 9p21,encodes proteins that act as tumor suppressors. Variantsat this site can alter the tumor suppressor function. The second gene, cyclin-dependent kinase 4 (CDK4), is an oncogene located on chromosome 12q13 and has been identified in about 6 families worldwide. A third gene, not fully characterized, maps to chromosome 1p22. The incidence of CDKN2A variants in the general population is very low. For example, it is estimated that in Queensland, Australia, an area with a high incidence of melanoma, only 0.2% of all patients with melanoma will harbor a CDKN2A variant. Variants are also infrequent in those with an early age of onset or those with multiple primary melanomas.However, the incidence of CDKN2A variants increases with a positive family history; CDKN2A variants will be found in 5% of families with first -degree relatives, rising to 20% to 40% in kindreds with 3 or more affected first-degree relatives.Variant detection rates in the CDKN2A gene are generally estimated as 20% to 25% in hereditary CMM but can vary between 2% and 50%, depending on the family history and population studied. Validated clinical risk prediction tools to assess the probability that an affected individual carries a germline CDKN2A variant are available.
Familial CMM has been described in families in which either 2 first -degree relatives are diagnosed with melanoma or a family with 3 melanoma patients, irrespective of the degree of relationship.Others have defined familial CMM as having at least 3 (first-, second-, or third-degree) affected members or 2 affected family members in which at least one was diagnosed before age 50 years, or pancreatic cancer occurred in a first-or second-degree relative or 1
member had multiple primary melanomas.Other malignancies associated with familial CMM, specifically those associated with CDKN2A variants, have been escribed. The most pronounced associated malignancy is pancreatic cancer. Other associated malignancies include other gastrointestinal malignancies, breast cancer, brain cancer, lymphoproliferative malignancies, and lung cancer. It is also important to recognize that other cancer susceptibility genes may be
involved in these families. In particular, germline BRCA2 gene variants have been described in families with melanoma and breast cancer, gastrointestinal cancer, pancreatic cancer, or prostate cancer.
CMM can occur either with or without a family history of multiple dysplastic nevi. Families with both CMM and multiple dysplastic nevi have been referred to as having familial atypical multiple mole and melanoma syndrome (FAMMM). This syndrome is difficult to define because there is no agreement on a standard phenotype, and dysplastic nevi occur in up to 50% of the general population. Atypical or dysplastic nevi are associated with an increased risk for CMM. Initially, the phenotypes of atypical nevi and CMM were thought to cosegregate in FAMMM families, leading to the assumption that a single genetic factor was responsible. However, it was subsequently shown that in families with CDKN2A variants , there were family members with multiple atypical nevi who were non-carriers of the CDKN2A familial variant. Thus, the nevus phenotype cannot be used to distinguish carriers from non -carriers of CMM susceptibility in these families.
Some common allele(s) are associated with increased susceptibility to CMM but have low to moderate penetrance. One gene of moderate penetrance is the Melanocortin 1 receptor gene (MC1R). Variants in this gene are relatively common and have low penetrance for CMM. This gene is associated with fair complexion, freckles, and red hair, all risk factors for CMM. Variants in MC1R also modify the CMM risk in families with CDKN2A variants.
.
Summary of Evidence
For individuals who have CMM and a family history of this disease who receive genetic testing for genes associated with familial CMM, the evidence includes genetic association studies correlating variants in certain genes and the risk of developing cutaneous melanoma. Relevant outcomes are overall survival, disease - specific survival, test accuracy, and test validity. Limitations with clinical validity include difficulties with variant interpretations, variable penetrance of a given variant, and residual risk with a benign variant. Currently, management of melanoma patients does not change based on genetic variants identified in genes associated with familial CMM, therefore, clinical utility is lacking. The evidence is insufficient to determine the effects of the technology on health outcomes.
For individuals who are asymptomatic and in a family at high -risk of developing CMM who receive genetic testing for genes associated with familial CMM, the evidence includes genetic association studies correlating variants in certain genes and the risk of developing CMM. Relevant outcomes are overall survival, disease-specific survival, test accuracy, and test validity. Limitations with clinical validity include difficulties with variant interpretations, variable
penetrance of a given variant, and residual risk with a benign variant. Currently, management of patients considered high risk for CMM focuses on the reduction of sun exposure, use of sunscreens, vigilant cutaneous surveillance of pigmented lesions, and prompt biopsy of suspicious lesions. It is unclear how genetic testing for variants associated with increased risk of CMM would alter these management recommendations; therefore, clinical utility is lacking. The evidence is insufficient to determine the effects of the technology on health outcomes.
Chromosomes are found in each cell and hold all of the genetic material —the DNA —of each person. Each cell usually contains 23 pairs of chromosomes, including the pair that determines the person’s sex. Having more or fewer chromosomes —known as aneuploidy —results in birth defects. Screening for aneuploidies is recommended during pregnancy. In the past, this screening was typically done by examining cells from the fetus. The cells were obtained either by taking a sample of the placenta or the amniotic fluid surrounding the baby. Newer tests that require only a blood sample from the mother can be used to screen for aneuploidies. This test looks at pieces of the fetus’s DNA that are naturally circulating in the mother’s blood. This policy describes when this type of blood test may be medically necessary. This blood test is investigational —unproven —when it’s used to look for missing pieces of chromosomes that are too small to be seen without a microscope. It’s also investigational when it’s used early in the pregnancy to look at the sex Chromosomes.
Note:
The Introduction section is for your general knowledge and is not to be taken as policy coverage criteria. The rest of the policy uses specific words and concepts familiar to medical professionals. It is intended for providers.A provider can be a person, such as a doctor, nurse, psychologist, or dentist. A provider also can be a place where medical care is given, like a hospital, clinic, or lab.This policy informs them about when a service may be covered.
Karyotyping would be necessary to exclude the possibility of a false -positive, nucleic acid sequencing–based test. Before testing, women should be counseled about the risk of a false-positive test.In Committee Opinion No. 640, the American College of Obstetricians and Gynecologists (2015) recommended that all patients receive information on the risks and benefits of various methods of prenatal screening and diagnostic testing for fetal aneuploidies, including the option of no testing.
Studies published to date on noninvasive prenatal screening for fetal aneuploidies have reported rare but occasional false-positives. False-positive findings have been found to be associated with factors including placental mosaicism, vanishing twins, and maternal malignancies. Diagnostic testing is necessary to confirm positive cell-free fetal DNA tests, and management decisions should not be based solely on the results of cell-free fetal DNA testing. The American College of Obstetricians and Gynecologists further recommended that patients with indeterminate or uninterpretable (ie, “no call”) cell -free fetal DNA test results be referred for genetic counseling and offered ultrasound evaluation and diagnostic testing because “no call” findings have been associated with an increased risk of aneuploidy
Cell -free fetal DNA screening does not assess risk of neural tube defects. Patients should continue to be offered ultrasound or maternal serum
*-fetoprotein screening.
Genetics Nomenclature Update
The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics (see Table 1). The Society’s nomenclature is recommended by the Human Variome Project, the HUman Genome Organization, and by the Human Genome Variation Society itself.The American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes.
Table 2 shows the recommended standard terminology—“pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign”—to describe variants identified that cause Mendelian disorders.
Genetic Counseling
Experts recommend formal genetic counseling for patients who are at risk for inherited disorders and who wish to undergo genetic testing.Interpretating the results of genetic tests and understanding risk factors can be difficult for some patients; genetic counseling helps individuals understand the impact of genetic testing, including the possible effects the test results could have on the individual or their family members. It should be noted that genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing; further, genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods
Description
National guidelines recommend that all pregnant women be offered screening for fetal chromosomal abnormalities, most of which are aneuploidies, an abnormal number of chromosomes. Trisomy syndromes are aneuploidies involving 3 copies of 1 chromosome. Trisomies 21 (T21), 18 (T18), and 13 (T13) are the most common forms of fetal aneuploidy. Fetuses with T18 and T13 generally do not survive to birth. There are numerous limitations to standard screening for these disorders using maternal serum and fetal ultrasound. Noninvasive prenatal screening (NIPS) analyzing cell-free fetal DNA in maternal serum is a potential complement or alternative to conventional serum screening. NIPS using cell-free fetal DNA has also been proposed to screen for microdeletions.
Fetal Aneuploidy
Fetal chromosomal abnormalities occur in approximately 1 in 160 live births. Most fetal chromosomal abnormalities are aneuploidies, defined as an abnormal number of chromosomes. The trisomy syndromes are aneuploidies involving 3 copies of 1 chromosome. The most important risk factor for trisomy syndromes is maternal age. The approximate risk of a trisomy 21 (T21; Down syndrome)*affected birth is 1 in 1100 at age 25 to 29. The risk of a fetus with T21 (at 16 weeks of gestation) is about 1 in 250 at age 35 and 1 in 75 at age 40.1T21 is the most common chromosomal aneuploidy and provides the impetus for current maternal serum screening programs. Other trisomy syndromes include T18 (Edwards syndrome) and T13 (Patau syndrome), which are the next most common forms of fetal aneuploidy, although the percentage of cases surviving to birth is low and survival beyond birth is limited. Detection of T18 and T13 early in pregnancy can facilitate preparation for fetal loss or early intervention.
Fetal Aneuploidy Screening
Standard aneuploidy screening involves combinations of maternal serum markers and fetal ultrasound done at various stages of pregnancy. The detection rate for various combinations of noninvasive testing ranges from 60% to 96% when the false-positive rate is set at 5%. When tests indicate a high risk of a trisomy syndrome, direct karyotyping of fetal tissue obtained by amniocentesis or chorionic villous sampling (CVS) is required to confirm that T21 or another trisomy is present. Both amniocentesis and CVS are invasive procedures and have procedure-associated risks of fetal injury, fetal loss, and infection.
A new screening strategy that reduces unnecessary amniocentesis and CVS procedures or increases detection of T21, T18, and T13 could improve outcomes. Confirmation of positive noninvasive screening tests with amniocentesis or CVS is recommended; with more accurate tests, fewer women would receive positive screening results.
Commercial, noninvasive, sequencing-based testing of maternal serum for fetal trisomy syndromes is now available. The testing technology involves detection of cell-free fetal DNA fragments present in the plasma of pregnant women. As early as 8 to 10 weeks of gestation, these fetal DNA fragments comprise 6% to 10% or more of the total cell -free DNA in a maternal plasma sample. The tests are unable to provide a result if the fetal fraction is too low, (ie,
Cell-Free Fetal DNA Analysis Methods4>
Sequencing-based tests use 1 of 2 general approaches to analyzing cell-free DNA. The first category of tests uses quantitative or counting methods. The most widely used technique to date uses massively parallel sequencing (MPS; also known as next-generation sequencing). DNA fragments are amplified by polymerase chain reaction; during the sequencing process, the amplified fragments are spatially segregated and sequenced simultaneously in a massively parallel fashion. Sequenced fragments can be mapped to the reference human genome to obtain numbers of fragment counts per chromosome. The sequencing-derived percent of fragments from the chromosome of interest reflects the chromosomal representation of the maternal and fetal DNA fragments in the original maternal plasma sample. Another technique is direct DNA analysis, which analyzes specific cell-free DNA fragments across samples and requires approximately a tenth the number of cell-free DNA fragments as MPS. The digital analysis of selected regions (DANSR™) is an assay that uses direct DNA analysis.
The second general approach is single nucleotide variant-based methods. These use targeted amplification and analysis of approximately 20,000 single nucleotide variants on selected chromosomes (eg, 21, 18, 13) in a single reaction. A statistical algorithm is used to determine the number of each type of chromosome. At least some of the commercially available cell-free fetal DNA prenatal tests also test for other abnormalities including sex chromosome abnormalities and selected microdeletions.
Copy Number Variants and Clinical Disorders
Microdeletions (also known as submicroscopic deletions) are chromosomal deletions that are too small to be detected by microscopy or conventional cytogenetic methods. They can be as small as 1 and 3 megabases long. Along with microduplications, microdeletions are collectively known as copy number variants. Copy number variants can lead to disease when the change in copy number of a dose-sensitive gene or genes disrupts the ability of the gene(s) to function and affects the amount of protein produced. A number of genomic disorders associated with microdeletion have been identified, which may be associated with serious clinical features, such as cardiac anomalies, immune deficiency, palatal defects, and developmental delay as in DiGeorge syndrome. Some of the syndromes (eg, DiGeorge) have complete penetrance yet marked variability in clinical expressivity. A contributing factor is that the breakpoints of the microdeletions may vary, and there may be a correlation between the number of haplo-insufficient genes and phenotypic severity.
CPT 81404 Molecular pathology procedure, Level 5 (eg, analysis of 2 - 5 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 6 -10 exons, or characterization of a dynamic mutation disorder/triplet repeat by Southern blot analysis)
0009M Fetal aneuploidy (trisomy 21 and 18) DNA sequence analysis of selected regions using maternal plasma, algorithm reported as a risk score for each trisomy
81420 Fetal chromosomal aneuploidy (eg, trisomy 21, monosomy X) genomic sequence analysis panel, circulating cell-free fetal DNA in maternal blood, must include analysis of chromosomes 13, 18 and 21
81422 Fetal chromosomal microdeletion(s) genomic sequence analysis (eg, DiGeorge syndrome, Cri-du-chat syndrome), circulating cell-free fetal DNA in maternal blood
81479 Unlisted molecular pathology procedure
81507 Fetal aneuploidy (trisomy 21, 18, and 13) DNA sequence analysis of selected regions using maternal plasma, algorithm reported as a risk score for each trisomy
81599 Unlisted chemistry procedure
84999 Unlisted chemistry procedure
Introduction
Melanoma is one type of skin cancer. It begins in the melanocyte cells of the skin. These cells produce a pigment(melanin) that gives the skin its color, all the way from pink to dark. Damage to the DNA in melanocytes can cause the cells to grow out of control, leading to melanoma. It’s believed the main cause of melanoma is too much exposure to ultraviolet light, such as getting bad sunburns or using tanning lamps. Another risk factor is family history.If one person has melanoma then there’s a greater chance that the parent, child, brother, or sister could also develop melanoma.For those at high risk of getting melanoma , medical experts say the best ways to reduce the risk are to limit sun exposure, use sunscreen, and watch for unusual moles or other unusually colored areas of the skin. Genetic tests have been created to look for genetic changes related to melanoma. But results from these genetic tests wouldn’t change recommendations for high risk people. Medical studies don’t show how genetic testing will lead to better health results. Genetic testing for melanoma is considered unproven .
Note:
The Introduction section is for your general knowledge and is not to be taken as policy coverage criteria. The rest of the policy uses specific words and concepts familiar to medical professionals. It is intended for providers.A provider can be a person, such as a doctor, nurse, psychologist, or dentist. A provider also can be a place where medical care is given, like a hospital, clinic,or lab.This policy informs them about when a service may be covered.
Genetics Nomenclature Update
The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics (see Table 1). The Society’s nomenclature is recommended by the Human Variome Project, the Human Genome Organization, and by the Human Genome Variation Society itself.
The American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table 2 shows the recommended standard terminology—“pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign”—to describe variants identified that cause Mendelian disorders
Genetic Counseling
Experts recommend formal genetic counseling for patients who are at risk for inherited disorders and who wish to undergo genetic testing. Interpreting the results of genetic tests and understanding risk factors can be difficult for some patients; genetic counseling helps individuals understand the impact of genetic testing, including the possible effects the test results could have on the individual or their family members. It should be noted that genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing; further, genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.
Benefit Application
Genetic testing for genes associated with cutaneous malignant melanoma will likely be performed at specialty laboratories.
Description
Cutaneous melanoma is the third most common type of skin cancer, but the most lethal. Some cases of cutaneous malignant melanoma are familial. Potential genetic markers for this disease are being evaluated in affected individuals with a family history of disease and in unaffected individuals in a high -risk family
Cutaneous Malignant Melanoma
A genetic predisposition to Cutaneous Malignant Melanoma (CMM)is suspected in these specific clinical situations:
*Melanoma has been diagnosed in multiple family members
*Multiple primary melanomas are identified in a single patient
*Melanomas began at an early age
A positive family history of melanoma is the most significant risk factor. It is estimated that approximately 10% of patients with melanoma have a first -or second -degree relative with melanoma. Although some of the familial risk may be related to shared environmental factors, 3 main genes involved in CMM susceptibility have been identified. Cyclin-dependent kinase inhibitor 2A (CDKN2A), located on chromosome 9p21,encodes proteins that act as tumor suppressors. Variantsat this site can alter the tumor suppressor function. The second gene, cyclin-dependent kinase 4 (CDK4), is an oncogene located on chromosome 12q13 and has been identified in about 6 families worldwide. A third gene, not fully characterized, maps to chromosome 1p22. The incidence of CDKN2A variants in the general population is very low. For example, it is estimated that in Queensland, Australia, an area with a high incidence of melanoma, only 0.2% of all patients with melanoma will harbor a CDKN2A variant. Variants are also infrequent in those with an early age of onset or those with multiple primary melanomas.However, the incidence of CDKN2A variants increases with a positive family history; CDKN2A variants will be found in 5% of families with first -degree relatives, rising to 20% to 40% in kindreds with 3 or more affected first-degree relatives.Variant detection rates in the CDKN2A gene are generally estimated as 20% to 25% in hereditary CMM but can vary between 2% and 50%, depending on the family history and population studied. Validated clinical risk prediction tools to assess the probability that an affected individual carries a germline CDKN2A variant are available.
Familial CMM has been described in families in which either 2 first -degree relatives are diagnosed with melanoma or a family with 3 melanoma patients, irrespective of the degree of relationship.Others have defined familial CMM as having at least 3 (first-, second-, or third-degree) affected members or 2 affected family members in which at least one was diagnosed before age 50 years, or pancreatic cancer occurred in a first-or second-degree relative or 1
member had multiple primary melanomas.Other malignancies associated with familial CMM, specifically those associated with CDKN2A variants, have been escribed. The most pronounced associated malignancy is pancreatic cancer. Other associated malignancies include other gastrointestinal malignancies, breast cancer, brain cancer, lymphoproliferative malignancies, and lung cancer. It is also important to recognize that other cancer susceptibility genes may be
involved in these families. In particular, germline BRCA2 gene variants have been described in families with melanoma and breast cancer, gastrointestinal cancer, pancreatic cancer, or prostate cancer.
CMM can occur either with or without a family history of multiple dysplastic nevi. Families with both CMM and multiple dysplastic nevi have been referred to as having familial atypical multiple mole and melanoma syndrome (FAMMM). This syndrome is difficult to define because there is no agreement on a standard phenotype, and dysplastic nevi occur in up to 50% of the general population. Atypical or dysplastic nevi are associated with an increased risk for CMM. Initially, the phenotypes of atypical nevi and CMM were thought to cosegregate in FAMMM families, leading to the assumption that a single genetic factor was responsible. However, it was subsequently shown that in families with CDKN2A variants , there were family members with multiple atypical nevi who were non-carriers of the CDKN2A familial variant. Thus, the nevus phenotype cannot be used to distinguish carriers from non -carriers of CMM susceptibility in these families.
Some common allele(s) are associated with increased susceptibility to CMM but have low to moderate penetrance. One gene of moderate penetrance is the Melanocortin 1 receptor gene (MC1R). Variants in this gene are relatively common and have low penetrance for CMM. This gene is associated with fair complexion, freckles, and red hair, all risk factors for CMM. Variants in MC1R also modify the CMM risk in families with CDKN2A variants.
.
Summary of Evidence
For individuals who have CMM and a family history of this disease who receive genetic testing for genes associated with familial CMM, the evidence includes genetic association studies correlating variants in certain genes and the risk of developing cutaneous melanoma. Relevant outcomes are overall survival, disease - specific survival, test accuracy, and test validity. Limitations with clinical validity include difficulties with variant interpretations, variable penetrance of a given variant, and residual risk with a benign variant. Currently, management of melanoma patients does not change based on genetic variants identified in genes associated with familial CMM, therefore, clinical utility is lacking. The evidence is insufficient to determine the effects of the technology on health outcomes.
For individuals who are asymptomatic and in a family at high -risk of developing CMM who receive genetic testing for genes associated with familial CMM, the evidence includes genetic association studies correlating variants in certain genes and the risk of developing CMM. Relevant outcomes are overall survival, disease-specific survival, test accuracy, and test validity. Limitations with clinical validity include difficulties with variant interpretations, variable
penetrance of a given variant, and residual risk with a benign variant. Currently, management of patients considered high risk for CMM focuses on the reduction of sun exposure, use of sunscreens, vigilant cutaneous surveillance of pigmented lesions, and prompt biopsy of suspicious lesions. It is unclear how genetic testing for variants associated with increased risk of CMM would alter these management recommendations; therefore, clinical utility is lacking. The evidence is insufficient to determine the effects of the technology on health outcomes.
Chromosomes are found in each cell and hold all of the genetic material —the DNA —of each person. Each cell usually contains 23 pairs of chromosomes, including the pair that determines the person’s sex. Having more or fewer chromosomes —known as aneuploidy —results in birth defects. Screening for aneuploidies is recommended during pregnancy. In the past, this screening was typically done by examining cells from the fetus. The cells were obtained either by taking a sample of the placenta or the amniotic fluid surrounding the baby. Newer tests that require only a blood sample from the mother can be used to screen for aneuploidies. This test looks at pieces of the fetus’s DNA that are naturally circulating in the mother’s blood. This policy describes when this type of blood test may be medically necessary. This blood test is investigational —unproven —when it’s used to look for missing pieces of chromosomes that are too small to be seen without a microscope. It’s also investigational when it’s used early in the pregnancy to look at the sex Chromosomes.
Note:
The Introduction section is for your general knowledge and is not to be taken as policy coverage criteria. The rest of the policy uses specific words and concepts familiar to medical professionals. It is intended for providers.A provider can be a person, such as a doctor, nurse, psychologist, or dentist. A provider also can be a place where medical care is given, like a hospital, clinic, or lab.This policy informs them about when a service may be covered.
Karyotyping would be necessary to exclude the possibility of a false -positive, nucleic acid sequencing–based test. Before testing, women should be counseled about the risk of a false-positive test.In Committee Opinion No. 640, the American College of Obstetricians and Gynecologists (2015) recommended that all patients receive information on the risks and benefits of various methods of prenatal screening and diagnostic testing for fetal aneuploidies, including the option of no testing.
Studies published to date on noninvasive prenatal screening for fetal aneuploidies have reported rare but occasional false-positives. False-positive findings have been found to be associated with factors including placental mosaicism, vanishing twins, and maternal malignancies. Diagnostic testing is necessary to confirm positive cell-free fetal DNA tests, and management decisions should not be based solely on the results of cell-free fetal DNA testing. The American College of Obstetricians and Gynecologists further recommended that patients with indeterminate or uninterpretable (ie, “no call”) cell -free fetal DNA test results be referred for genetic counseling and offered ultrasound evaluation and diagnostic testing because “no call” findings have been associated with an increased risk of aneuploidy
Cell -free fetal DNA screening does not assess risk of neural tube defects. Patients should continue to be offered ultrasound or maternal serum
*-fetoprotein screening.
Genetics Nomenclature Update
The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics (see Table 1). The Society’s nomenclature is recommended by the Human Variome Project, the HUman Genome Organization, and by the Human Genome Variation Society itself.The American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes.
Table 2 shows the recommended standard terminology—“pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign”—to describe variants identified that cause Mendelian disorders.
Genetic Counseling
Experts recommend formal genetic counseling for patients who are at risk for inherited disorders and who wish to undergo genetic testing.Interpretating the results of genetic tests and understanding risk factors can be difficult for some patients; genetic counseling helps individuals understand the impact of genetic testing, including the possible effects the test results could have on the individual or their family members. It should be noted that genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing; further, genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods
Description
National guidelines recommend that all pregnant women be offered screening for fetal chromosomal abnormalities, most of which are aneuploidies, an abnormal number of chromosomes. Trisomy syndromes are aneuploidies involving 3 copies of 1 chromosome. Trisomies 21 (T21), 18 (T18), and 13 (T13) are the most common forms of fetal aneuploidy. Fetuses with T18 and T13 generally do not survive to birth. There are numerous limitations to standard screening for these disorders using maternal serum and fetal ultrasound. Noninvasive prenatal screening (NIPS) analyzing cell-free fetal DNA in maternal serum is a potential complement or alternative to conventional serum screening. NIPS using cell-free fetal DNA has also been proposed to screen for microdeletions.
Fetal Aneuploidy
Fetal chromosomal abnormalities occur in approximately 1 in 160 live births. Most fetal chromosomal abnormalities are aneuploidies, defined as an abnormal number of chromosomes. The trisomy syndromes are aneuploidies involving 3 copies of 1 chromosome. The most important risk factor for trisomy syndromes is maternal age. The approximate risk of a trisomy 21 (T21; Down syndrome)*affected birth is 1 in 1100 at age 25 to 29. The risk of a fetus with T21 (at 16 weeks of gestation) is about 1 in 250 at age 35 and 1 in 75 at age 40.1T21 is the most common chromosomal aneuploidy and provides the impetus for current maternal serum screening programs. Other trisomy syndromes include T18 (Edwards syndrome) and T13 (Patau syndrome), which are the next most common forms of fetal aneuploidy, although the percentage of cases surviving to birth is low and survival beyond birth is limited. Detection of T18 and T13 early in pregnancy can facilitate preparation for fetal loss or early intervention.
Fetal Aneuploidy Screening
Standard aneuploidy screening involves combinations of maternal serum markers and fetal ultrasound done at various stages of pregnancy. The detection rate for various combinations of noninvasive testing ranges from 60% to 96% when the false-positive rate is set at 5%. When tests indicate a high risk of a trisomy syndrome, direct karyotyping of fetal tissue obtained by amniocentesis or chorionic villous sampling (CVS) is required to confirm that T21 or another trisomy is present. Both amniocentesis and CVS are invasive procedures and have procedure-associated risks of fetal injury, fetal loss, and infection.
A new screening strategy that reduces unnecessary amniocentesis and CVS procedures or increases detection of T21, T18, and T13 could improve outcomes. Confirmation of positive noninvasive screening tests with amniocentesis or CVS is recommended; with more accurate tests, fewer women would receive positive screening results.
Commercial, noninvasive, sequencing-based testing of maternal serum for fetal trisomy syndromes is now available. The testing technology involves detection of cell-free fetal DNA fragments present in the plasma of pregnant women. As early as 8 to 10 weeks of gestation, these fetal DNA fragments comprise 6% to 10% or more of the total cell -free DNA in a maternal plasma sample. The tests are unable to provide a result if the fetal fraction is too low, (ie,
Cell-Free Fetal DNA Analysis Methods4>
Sequencing-based tests use 1 of 2 general approaches to analyzing cell-free DNA. The first category of tests uses quantitative or counting methods. The most widely used technique to date uses massively parallel sequencing (MPS; also known as next-generation sequencing). DNA fragments are amplified by polymerase chain reaction; during the sequencing process, the amplified fragments are spatially segregated and sequenced simultaneously in a massively parallel fashion. Sequenced fragments can be mapped to the reference human genome to obtain numbers of fragment counts per chromosome. The sequencing-derived percent of fragments from the chromosome of interest reflects the chromosomal representation of the maternal and fetal DNA fragments in the original maternal plasma sample. Another technique is direct DNA analysis, which analyzes specific cell-free DNA fragments across samples and requires approximately a tenth the number of cell-free DNA fragments as MPS. The digital analysis of selected regions (DANSR™) is an assay that uses direct DNA analysis.
The second general approach is single nucleotide variant-based methods. These use targeted amplification and analysis of approximately 20,000 single nucleotide variants on selected chromosomes (eg, 21, 18, 13) in a single reaction. A statistical algorithm is used to determine the number of each type of chromosome. At least some of the commercially available cell-free fetal DNA prenatal tests also test for other abnormalities including sex chromosome abnormalities and selected microdeletions.
Copy Number Variants and Clinical Disorders
Microdeletions (also known as submicroscopic deletions) are chromosomal deletions that are too small to be detected by microscopy or conventional cytogenetic methods. They can be as small as 1 and 3 megabases long. Along with microduplications, microdeletions are collectively known as copy number variants. Copy number variants can lead to disease when the change in copy number of a dose-sensitive gene or genes disrupts the ability of the gene(s) to function and affects the amount of protein produced. A number of genomic disorders associated with microdeletion have been identified, which may be associated with serious clinical features, such as cardiac anomalies, immune deficiency, palatal defects, and developmental delay as in DiGeorge syndrome. Some of the syndromes (eg, DiGeorge) have complete penetrance yet marked variability in clinical expressivity. A contributing factor is that the breakpoints of the microdeletions may vary, and there may be a correlation between the number of haplo-insufficient genes and phenotypic severity.
