Genetic Testing And Counseling In Hereditary Breast And Ovarian Cancer Syndrome

Genetic testing for HBOC has become generally accepted as part of standard clinical practice and should be offered to any patient that has personal or family history features suggestive of HBOC (Table 3) and when genetic testing results could influence the medical management of that patient or the patient's family members. Clinical laboratories employ a variety of molecular techniques to detect germline mutations in BRCA1 and BRCA2 in a peripheral blood sample (Table 4). The sensitivity of molecular testing for BRCA cancer-predisposing mutations is

Table 1 Syndromes associated with hereditary breast and/or ovarian cancer

Hereditary cancer syndrome

Associated tumor suppressor genes or oncogenes

Associated malignancies

Hereditary breast and BRCA1

ovarian cancer BRCA2

Li-Fraumeni P53

Cowden's disease PTEN

Peutz-Jegher STK11/LKP1

Ataxia telangiectasia

Hereditary diffuse gastric cancer Hereditary nonpolyposis colorectal cancer

Gorlin (nevoid basal-cell carcinoma)

Multiple endocrine RET oncogene neoplasia type 1

ATM (autosomal recessive) CDH1

Mismatch repair genes (MSH2, MLH1, PMS1, PMS2, MSH3, MSH5, MSH6) PTCH

Breast, ovarian, colon, and prostate cancer Breast, ovarian, prostate, pancreatic, bile duct and gall bladder, stomach cancer, and malignant melanoma Soft-tissue sarcomas, breast cancer, brain tumors, acute leukemia, and other epithelial and mesenchymal tumors Breast cancer, thyroid cancer, and colonic neoplasms

Colorectal cancer, ovarian stromal tumors, uterine and cervical cancer

GI tract polyposis and cancers, breast, testis, cancers Lymphoma, leukemia, breast cancer, and other solid malignancies

Gastric cancer and lobular breast cancer in females Colorectal, endometrial, ovarian, stomach, uroepithelial, hepatobiliary, brain, and small bowel cancers

Basal-cell carcinoma, medulloblastoma, ovarian calcifications and fibroma, and leiomyosarcoma

Parathyroid hyperplasia, gastrinoma, and pituitary neoplasms dependent on the method used for analysis and the a priori risk of the person tested to have a mutation in either gene based on the person's cancer history, family history, and ethnic background. No currently available technique can guarantee the identification of all cancer-predisposing mutations in the BRCA1 or BRCA2 genes.[2] The molecular method with the highest level of sensitivity in situations where a familial mutation has not yet been identified is DNA sequencing. Mutation-specific clinical testing is utilized primarily for the three Ashkenazi Jewish founder mutations, which include 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2, as well as in families in which a mutation has previously been identified. Clinical interpretation of the results of genetic testing is divided into three categories: positive (a deleterious mutation is detected), negative (no mutation is detected), and uninformative (a variant of unknown clinical significance is detected). The only truly informative

Table 2 Estimated lifetime risks of BRCA1- and BRCA2-associated malignancies


Associated malignancy

Risk to age 70 in mutation carriers


Female breast


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