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Indications and Management of Genetic Testing
Lisa Madlensky, PhD, CGC
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KEY FACTS

  • Testing and Interventions

    • Patients Appropriate for Testing

      TERMINOLOGY

      • Definitions

        • Germline mutation: Identified in inherited genetic material in normal cells, used for germline genetic testing (typically sourced from blood or saliva)
        • Somatic/tumor mutation: Found only in tumor DNA, not inherited
        • Penetrance: Proportion of individuals with given pathogenic gene mutation that show diseased phenotype
        • Pathogenic/likely pathogenic mutation: Variant in DNA that is known to be disease causing; positive genetic test
        • Variant of unknown significance (VUS)
          • Found in DNA, may or may not be disease causing
          • Generally, no clinical action is taken for VUS
          • Over time, some are reclassified as pathogenic, but most are benign
        • Personal/family history of ovarian cancer
          • Fallopian tube and primary peritoneal cancer
          • Invasive epithelial ovarian cancers
            • i.e., exclude germ cell ovarian cancers
        • Personal/family history of aggressive/metastatic prostate cancer: Includes Gleason 7 or higher tumors &/or proven metastatic prostate cancer (not based on PSA levels alone)
        • Personal/family history of pancreatic cancer: Includes adenocarcinoma; excludes endocrine tumors of pancreas
        • Single nucleotide polymorphism (SNP): Small variation in DNA sequence; most are common, but some are rare; may or may not impact disease risk

      CLINICAL IMPLICATIONS

      • Clinical Importance

        • Importance for Family Members

          High Risk of Breast Cancer

          • BRCA1/2, ATM, CHEK2, PALB2

            • Breast Cancer Patients

              • Women Without Personal Cancer Diagnosis

                Rare Cancer Syndromes

                • Principles of Genetic Testing for Rare Syndromes

                  • Hereditary Diffuse Gastric Cancer (CDH1 Gene)

                    • Li-Fraumeni Syndrome (TP53 Gene)

                      • Peutz-Jeghers Syndrome (STK11 Gene)

                        • PTEN Hamartoma Tumor Syndrome

                          • Neurofibromatosis Type 1 (NF1)

                            Considerations in Genetic Testing

                            • Many Types of Clinical Genetic Testing Available

                              • Population-Based Genetic Testing

                                • Informed Consent for Germline Genetic Testing

                                  • Sample Types for Genetic Testing

                                    Selected References

                                    1. NCCN: Genetics Screening. https://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf. Accessed April 6, 2019
                                    2. Beitsch PD et al: Underdiagnosis of Hereditary Breast Cancer: Are Genetic Testing Guidelines a Tool or an Obstacle? J Clin Oncol. 37(6):453-460, 2019
                                    3. Corso G et al: Hereditary lobular breast cancer with an emphasis on E-cadherin genetic defect. J Med Genet. 55(7):431-41, 2018
                                    4. Schon K et al: Clinical implications of germline mutations in breast cancer: TP53. Breast Cancer Res Treat. 167(2):417-23, 2018
                                    5. Afghahi A et al: The changing landscape of genetic testing for inherited breast cancer predisposition. Curr Treat Options Oncol. 18(5):27, 2017
                                    6. Couch FJ et al: Associations between cancer predisposition testing panel genes and breast cancer. JAMA Oncol. 3(9):1190-6, 2017
                                    7. Daly MB et al: NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Breast and Ovarian, Version 2.2017. J Natl Compr Canc Netw. 15(1):9-20, 2017
                                    8. Howell SJ et al: Increased risk of breast cancer in neurofibromatosis type 1: current insights. Breast Cancer (Dove Med Press). 9:531-6, 2017
                                    9. Lieberman S et al: Population screening for BRCA1/BRCA2 mutations: lessons from qualitative analysis of the screening experience. Genet Med. 19(6):628-34, 2017
                                    10. Slavin TP et al: The contribution of pathogenic variants in breast cancer susceptibility genes to familial breast cancer risk. NPJ Breast Cancer. 3:22, 2017
                                    11. Kurian AW et al: Refining breast cancer risk stratification: additional genes, additional information. Am Soc Clin Oncol Educ Book. 35:44-56, 2016
                                    12. Mai PL et al: Risks of first and subsequent cancers among TP53 mutation carriers in the National Cancer Institute Li-Fraumeni syndrome cohort. Cancer. 122(23):3673-81, 2016
                                    13. Antoniou AC et al: Breast-cancer risk in families with mutations in PALB2. N Engl J Med. 371(6):497-506, 2014
                                    14. Robson ME et al: American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol. 28(5):893-901, 2010
                                    15. Eng C et al: PTEN Hamartoma Tumor Syndrome, updated June 12, 2016, in Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews®[Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018
                                    16. McGarrity TJ et al: Peutz-Jeghers Syndrome in Gene Reviews, Adam MP, Ardinger HH, Pagon RA, et al., editors. Seattle (WA): University of Washington, Seattle; 1993-2018.
                                    17. Petrucelli N et al: BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer in Gene Reviews, Adam MP, Ardinger HH, Pagon RA, et al., editors. Seattle (WA): University of Washington, Seattle; 1993-2018.
                                    18. Genetic Information Non-discrimination Act
                                    19. Kaurah P et al: Hereditary Diffuse Gastric Cancer in Gene Reviews, Adam MP, Ardinger HH, Pagon RA, et al., editors. Seattle (WA): University of Washington, Seattle; 1993-2018.
                                    Related Anatomy
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                                    References
                                    Tables

                                    Tables

                                    KEY FACTS

                                    • Testing and Interventions

                                      • Patients Appropriate for Testing

                                        TERMINOLOGY

                                        • Definitions

                                          • Germline mutation: Identified in inherited genetic material in normal cells, used for germline genetic testing (typically sourced from blood or saliva)
                                          • Somatic/tumor mutation: Found only in tumor DNA, not inherited
                                          • Penetrance: Proportion of individuals with given pathogenic gene mutation that show diseased phenotype
                                          • Pathogenic/likely pathogenic mutation: Variant in DNA that is known to be disease causing; positive genetic test
                                          • Variant of unknown significance (VUS)
                                            • Found in DNA, may or may not be disease causing
                                            • Generally, no clinical action is taken for VUS
                                            • Over time, some are reclassified as pathogenic, but most are benign
                                          • Personal/family history of ovarian cancer
                                            • Fallopian tube and primary peritoneal cancer
                                            • Invasive epithelial ovarian cancers
                                              • i.e., exclude germ cell ovarian cancers
                                          • Personal/family history of aggressive/metastatic prostate cancer: Includes Gleason 7 or higher tumors &/or proven metastatic prostate cancer (not based on PSA levels alone)
                                          • Personal/family history of pancreatic cancer: Includes adenocarcinoma; excludes endocrine tumors of pancreas
                                          • Single nucleotide polymorphism (SNP): Small variation in DNA sequence; most are common, but some are rare; may or may not impact disease risk

                                        CLINICAL IMPLICATIONS

                                        • Clinical Importance

                                          • Importance for Family Members

                                            High Risk of Breast Cancer

                                            • BRCA1/2, ATM, CHEK2, PALB2

                                              • Breast Cancer Patients

                                                • Women Without Personal Cancer Diagnosis

                                                  Rare Cancer Syndromes

                                                  • Principles of Genetic Testing for Rare Syndromes

                                                    • Hereditary Diffuse Gastric Cancer (CDH1 Gene)

                                                      • Li-Fraumeni Syndrome (TP53 Gene)

                                                        • Peutz-Jeghers Syndrome (STK11 Gene)

                                                          • PTEN Hamartoma Tumor Syndrome

                                                            • Neurofibromatosis Type 1 (NF1)

                                                              Considerations in Genetic Testing

                                                              • Many Types of Clinical Genetic Testing Available

                                                                • Population-Based Genetic Testing

                                                                  • Informed Consent for Germline Genetic Testing

                                                                    • Sample Types for Genetic Testing

                                                                      Selected References

                                                                      1. NCCN: Genetics Screening. https://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf. Accessed April 6, 2019
                                                                      2. Beitsch PD et al: Underdiagnosis of Hereditary Breast Cancer: Are Genetic Testing Guidelines a Tool or an Obstacle? J Clin Oncol. 37(6):453-460, 2019
                                                                      3. Corso G et al: Hereditary lobular breast cancer with an emphasis on E-cadherin genetic defect. J Med Genet. 55(7):431-41, 2018
                                                                      4. Schon K et al: Clinical implications of germline mutations in breast cancer: TP53. Breast Cancer Res Treat. 167(2):417-23, 2018
                                                                      5. Afghahi A et al: The changing landscape of genetic testing for inherited breast cancer predisposition. Curr Treat Options Oncol. 18(5):27, 2017
                                                                      6. Couch FJ et al: Associations between cancer predisposition testing panel genes and breast cancer. JAMA Oncol. 3(9):1190-6, 2017
                                                                      7. Daly MB et al: NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Breast and Ovarian, Version 2.2017. J Natl Compr Canc Netw. 15(1):9-20, 2017
                                                                      8. Howell SJ et al: Increased risk of breast cancer in neurofibromatosis type 1: current insights. Breast Cancer (Dove Med Press). 9:531-6, 2017
                                                                      9. Lieberman S et al: Population screening for BRCA1/BRCA2 mutations: lessons from qualitative analysis of the screening experience. Genet Med. 19(6):628-34, 2017
                                                                      10. Slavin TP et al: The contribution of pathogenic variants in breast cancer susceptibility genes to familial breast cancer risk. NPJ Breast Cancer. 3:22, 2017
                                                                      11. Kurian AW et al: Refining breast cancer risk stratification: additional genes, additional information. Am Soc Clin Oncol Educ Book. 35:44-56, 2016
                                                                      12. Mai PL et al: Risks of first and subsequent cancers among TP53 mutation carriers in the National Cancer Institute Li-Fraumeni syndrome cohort. Cancer. 122(23):3673-81, 2016
                                                                      13. Antoniou AC et al: Breast-cancer risk in families with mutations in PALB2. N Engl J Med. 371(6):497-506, 2014
                                                                      14. Robson ME et al: American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol. 28(5):893-901, 2010
                                                                      15. Eng C et al: PTEN Hamartoma Tumor Syndrome, updated June 12, 2016, in Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews®[Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018
                                                                      16. McGarrity TJ et al: Peutz-Jeghers Syndrome in Gene Reviews, Adam MP, Ardinger HH, Pagon RA, et al., editors. Seattle (WA): University of Washington, Seattle; 1993-2018.
                                                                      17. Petrucelli N et al: BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer in Gene Reviews, Adam MP, Ardinger HH, Pagon RA, et al., editors. Seattle (WA): University of Washington, Seattle; 1993-2018.
                                                                      18. Genetic Information Non-discrimination Act
                                                                      19. Kaurah P et al: Hereditary Diffuse Gastric Cancer in Gene Reviews, Adam MP, Ardinger HH, Pagon RA, et al., editors. Seattle (WA): University of Washington, Seattle; 1993-2018.