Who in the room would offer BRCA1/2 testing to this patient Who in the room would offer BRCA1/2 testing to this patient? How might the medical management change for this patient if she were positive for a mutation? Negative? Teaching points: BRCA1/2 are inherited in an autosomal dominant manner, thus they can be passed on through the maternal and the paternal lineage. The United States Preventative Services Task Force recommendation states that unaffected adult women who meet certain guidelines are appropriate for evaluation and testing of BRCA mutations. A negative test result in an unaffected patient rules out most causes of hereditary breast and ovarian cancer; however, testing of additional affected family members may clarify this risk further. Patient’s management will be based upon family history. References: US Preventive Services Task Force. Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility. Ann Intern Med. 2005;143:355-61.

Tyrer Cuzick factors – first menstruation = 12 years, age of first live birth = 24 years, no breast biopsy Tyrer Cuzick Model as recommended by ACS for MRI Guidelines http://www.ems-trials.org/riskevaluator/. The T-C model takes into account family and personal of breast and ovarian cancer. It also takes into account hormonal factors, such as age of menarche and childbearing history. This model also can account for previous biopsies and genetic test results. For this specific history, the lifetime risk of breast cancer taking into account family history and the negative BRCA test results is 14.4%. This is compared to the general population risk of 9.5%, as per the model. This patient does not meet the ACS criteria for breast MRI screening. References available online at www.myriadtests.com/provider/siter.htm

Who in the room would offer BRCA1/2 testing to this patient Who in the room would offer BRCA1/2 testing to this patient? How might the medical management change for this patient if she were positive for a mutation? Negative? Teaching Points: The United States Preventative Services Task Force recommendation states that unaffected adult women who meet certain guidelines are appropriate for evaluation and testing of BRCA mutations. A negative test result in an unaffected patient rules out most causes of hereditary breast and ovarian cancer, however, testing of additional affected family members may clarify this risk further. Patient’s management will be based upon family history. References: US Preventive Services Task Force. Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility. Ann Intern Med. 2005;143:355-61.

Tyrer Cuzick factors – first menstruation = 12 years, age of first live birth = 26 years, no breast biopsy Tyrer Cuzick Model as recommended by ACS for MRI Guidelines http://www.ems-trials.org/riskevaluator/. The T-C model takes into account family and personal of breast and ovarian cancer. It also takes into account hormonal factors, such as age of menarche and childbearing history. This model also can account for previous biopsies and genetic test results. For this specific history, the lifetime risk of breast cancer taking into account family history and the negative BRCA test results is 21.9%. This is compared to the general population risk of 10.2% for the general population, as per the model. This patient meets the ACS criteria for breast MRI screening. References available online at www.myriadtests.com/provider/siter.htm

Case # 3 Case Type: Hereditary Breast and Ovarian Cancer Syndrome (phenocopy) Questions: What are the Red Flags in this case? Who in the room would offer BRCA1/2 testing to this patient? How might the medical management change for this patient if she were positive for a mutation? How might the medical management change for this patient if she were negative for mutations?

Case # 3 Case Type: Hereditary Breast and Ovarian Cancer Syndrome (phenocopy) Teaching Points: Phenocopy: There are multiple ways to define phenocopy in the field of genetics. Essentially it refers to an individual in a family that has acquired the disease, in this case breast cancer, by sporadic causes versus the genetic causes segregating in the family. 1,2 Consider a referral to a Genetic Specialist. References: Lescai F, Franceschi C. The impact of phenocopy on the Genetic Analysis of Complex Traits. PLoS ONE. 2010. 5:7 Rannala B et al High-resolution multipoint linage-disequilibrium mapping in the context of a human genome sequence. Am J hum Genet 2001. 69: 159-178.

Case # 3 Case Type: Hereditary Breast and Ovarian cancer (phenocopy) References: http://myriadresourceguide.com/bracanal/risk.htm NCCN Clinical Practice Guidelines in Oncology: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp (Genetic/Familial High-Risk Assessment: Breast and Ovarian; Breast Cancer Screening and Diagnosis)

Case # 3 Case Type: Hereditary Breast and Ovarian Cancer Syndrome (phenocopy) So, in this case, the patient’s diagnosis of breast cancer is sporadic (a phenocopy), even though there is a hereditary predisposition to breast cancer in this family (which the patient did not inherit).

Case 4 Case Type: Testing Strategy for Ashkenazi Jewish Patients Questions: What are the Red Flags in this case? Who in the room would offer BRCA1/2 testing to this patient? How might the medical management change for this patient if she were positive for a mutation? How might the medical management change for this patient if she were negative for a mutation?

Case 4 Case Type: Testing Strategy for Ashkenazi Jewish Patients References http://myriadresourceguide.com/bracanal/risk.htm

Case 4 Case Type: Testing Strategy for Ashkenazi Jewish Patients Teaching points: If there is a reported mutation in the family, it’s important to make every attempt to get a copy of the report to ensure that testing is ordered appropriately. If it is impossible to get a copy of the report, it may be important to consider full sequencing and large rearrangement analysis of the genes. Guidelines recommend testing for all three AJ founder mutations even in a family where the mutation is known due to the high prevalence of the three founder mutations in the Ashkenazi Jewish population. Having a BRCA1 and BRCA2 mutation does not add to your cancer risk above a single mutation. References NCCN Clinical Practice Guidelines in Oncology, Genetics/Familial High –Risk Assessment: Breast and Ovarian v.1.2010

Case 5 Family history of late onset cancers Questions: What are the Red Flags in this case? Who in the room would offer BRCA1/2 testing to this patient? Who would offer Lynch testing for this patient? Would you tests (a) BRCA first (b) Lynch first (c ) test concurrently?

Case 5 Family history of late onset cancers Despite a family history of cancers, this patient doesn’t meet any published criteria for genetic testing. Patient is still at increased risk for cancers found in the family, but this is more representative of a family with sporadic/environmental cancers.