Couch [41]	Shattuck-Eidens [106]	Frank [108]	Parmigiani [111,120]
CSGE = conformation sensitive gel electrophoresis
Gene	BRCA1	BRCA1	BRCA1 and BRCA2	BRCA1 and BRCA2
Study population	169 women with breast cancer and family history of breast cancer and/or ovarian cancer	798 women with either early-onset breast cancer or ovarian cancer, or with family history of breast or ovarian cancer	238 women with breast cancer diagnosed at age <50 years or with ovarian cancer, with at least 1 first-degree or second-degree relative with breast cancer, aged <50 years, or ovarian cancer	Statistical model (BRCAPRO)
Proband characteristics	Proband may or may not have breast or ovarian cancer	Proband must be affected with breast cancer and/or ovarian cancer	Proband must be affected with breast cancer at age <50 years or ovarian cancer	Proband may or may not have breast or ovarian cancer
		Takes into account bilateral breast cancer and age of onset of proband	Takes into account probands with bilateral breast cancer and those with both breast and ovarian cancer	Consideration of proband’s current age or age at diagnosis of breast or ovarian cancer
			Special consideration for probands with breast cancer, aged <40 years	Takes into account: -Oophorectomy status
				- Bilateral breast cancer and those with breast cancer, ovarian cancer, or breast and ovarian cancer at any age
				- Male breast cancer
				- BRCA1/2 mutation status
Family history characteristics	Family must have >2 cases of breast cancer	May or may not have affected relatives	Must have first-degree relative with breast cancer, aged <50 years, or ovarian cancer	Includes all first-degree relatives and second-degree relatives with and without cancer
	Takes into account proband or relatives with breast and/or ovarian cancer	Takes into account relatives with breast and/or ovarian cancer	Takes into account additional relatives with breast cancer, aged <50 years, or ovarian cancer	Takes into account: -Oophorectomy status
	Uses average age at diagnosis of breast cancers	Does not take into account age of onset of cancer or bilateral breast cancer in relatives		- Relatives with male or female breast cancer
	Takes into account Ashkenazi Jewish ancestry	Takes into account Ashkenazi Jewish ancestry		- Female relatives with ovarian cancer or breast and ovarian cancer
				- Current age or age at death and age at diagnosis of breast cancer and ovarian cancer
				- Ashkenazi Jewish ancestry
				- BRCA1/2 mutation status
Provides risk estimate for	Composite family probability	Proband (who has breast or ovarian cancer)	Proband (who has breast cancer, aged <50 years, or ovarian cancer)	Any affected or unaffected family member
Limitations	Does not estimate likelihood of BRCA2 mutation	Does not estimate likelihood of BRCA2 mutation	Not applicable to women diagnosed with breast cancer at ≥50 years	Requires computer software and time-consuming data entry
	Not applicable to families with site-specific ovarian cancer	Further calculation required for unaffected relatives	Further calculation required for unaffected relatives	Incorporates only first-degree relatives and second-degree relatives; may need to change proband to best capture risk
	Does not take into account bilaterality or male breast cancer	Underestimates risk with multiple affected members	Combined data for Ashkenazi Jewish and non-Jewish families so it may overestimate risk for non-Jewish probands and underestimate risk for Jewish probands	Has been validated in a high-risk genetic counseling clinic [121]
	Some estimates are based on small sample size			Validity in moderate family histories unknown
	Further calculation required for unaffected relatives
	Because testing used CSGE, may underestimate mutation likelihood
Best application	Families with 1 or more cases of breast cancer, Ashkenazi Jewish families, and families with multiple affected members	Families with small number of affected members	Families with 2 first-degree relatives with breast cancer, aged <50 years, or ovarian cancer	Widely applicable. Performs equally well in African American families as in Caucasian families[27]
			Provides likelihood of either BRCA1 or BRCA2 mutation	Only model to incorporate unaffected relatives, male breast cancer, bilateral breast cancer, and age at diagnosis for all affected individuals
				Provides likelihood of either BRCA1 or BRCA2 mutation
				Program also provides Couch, Shattuck-Eidens and Frank risk estimates

References

27. Nanda R, Schumm LP, Cummings S, et al.: Genetic testing in an ethnically diverse cohort of high-risk women: a comparative analysis of BRCA1 and BRCA2 mutations in American families of European and African ancestry. JAMA 294 (15): 1925-33, 2005.  [PUBMED Abstract]
    
    
41. Couch FJ, DeShano ML, Blackwood MA, et al.: BRCA1 mutations in women attending clinics that evaluate the risk of breast cancer. N Engl J Med 336 (20): 1409-15, 1997.  [PUBMED Abstract]
    
    
106. Shattuck-Eidens D, Oliphant A, McClure M, et al.: BRCA1 sequence analysis in women at high risk for susceptibility mutations. Risk factor analysis and implications for genetic testing. JAMA 278 (15): 1242-50, 1997.  [PUBMED Abstract]
     
     
108. Frank TS, Manley SA, Olopade OI, et al.: Sequence analysis of BRCA1 and BRCA2: correlation of mutations with family history and ovarian cancer risk. J Clin Oncol 16 (7): 2417-25, 1998.  [PUBMED Abstract]
     
     
111. Parmigiani G, Berry D, Aguilar O: Determining carrier probabilities for breast cancer-susceptibility genes BRCA1 and BRCA2. Am J Hum Genet 62 (1): 145-58, 1998.  [PUBMED Abstract]
     
     
120. Katki HA: Incorporating medical interventions into carrier probability estimation for genetic counseling. BMC Med Genet 8: 13, 2007.  [PUBMED Abstract]
     
     
121. Berry DA, Iversen ES Jr, Gudbjartsson DF, et al.: BRCAPRO validation, sensitivity of genetic testing of BRCA1/BRCA2, and prevalence of other breast cancer susceptibility genes. J Clin Oncol 20 (11): 2701-12, 2002.  [PUBMED Abstract]