#1096 Background: The US Preventive Services Task Force (USPSTF) recommends that women with family histories suggesting increased risk of hereditary breast-ovarian cancer (HBOC) be referred to genetic counseling. Feasible methods for family history risk assessment are needed in order to implement this guideline. This study is conducted to assess the feasibility of using a computer-assisted family history tool to identify appropriate candidates for genetics referral among women seen in a multispecialty breast diagnostic center. Material and Methods: The Web-based Genetic Risk Easy Assessment Tool (GREAT) uses a validated, self-administered questionnaire to collect personal and family history of cancer. It connects with CancerGene to calculate breast cancer risks by Gail, Claus, and BRCA-PRO models and BRCA mutation probabilities. Validated algorithms in GREAT identify increased risk of HBOC according to USPSTF criteria, modified to include women with breast cancer. It provides a personalized report including cancer risk and prevention messages and a family tree. We invited consecutive women obtaining mammograms or consultations at the UH Breast Center to use the GREAT and obtained users' immediate feedback about the Website and personal report. Each user's responses were evaluated by genetics professionals to determine whether genetics referral would be indicated, and whether the woman herself or a living relative would be appropriate for genetic cancer susceptibility testing. Preliminary Results (participant enrollment is ongoing): 2065 women, mean age 57, were invited in the first 5 months of 2008. 22% had breast or ovarian cancer, 30% had a relative with breast or ovarian cancer, and 48% had no family or personal history. 194 women returned questionnaires to decline participation (mean age 56, 43% African-American); 37% did not have a computer or internet access, and 26% were concerned about privacy and internet security. 105 women consented and 67 so far had completed the GREAT (mean age 60, 16% African-American, 22% with a history of breast cancer). 28% of GREAT users received reports indicating increased risk for HBOC; all were considered appropriate for genetic counseling. >90% of users found the website easy to navigate, the questionnaire and personal report easy to understand, and the time taken not too long; none found the process upsetting. Most participants planned to talk with family members and show the report to relatives. Discussion: A self-selected, higher-risk group of women found the web-based GREAT an acceptable means of personal and familial cancer risk assessment in the context of a visit to the Breast Center. Lack of internet access and concerns about internet security posed barriers for some would-be participants. If analyses confirm the sensitivity and specificity of risk algorithms, providing access to this tool at the time of mammography may increase the feasibility of identifying and referring women for genetic consultation regarding hereditary breast-ovarian cancer susceptibility. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1096.

Knowledge of the clinical spectrum of rare genetic disorders helps in disease management and variant pathogenicity interpretation. Leveraging electronic health record (EHR)-linked genetic testing data from the eMERGE network, we determined the associations between a set of 23 hereditary cancer genes and 3017 phenotypes in 23544 individuals. This phenome-wide association study replicated 45% (184/406) of known gene-phenotype associations (P = 5.1 ×10-125). Meta-analysis with an independent EHR-derived cohort of 3242 patients confirmed 14 novel associations with phenotypes in the neoplastic, genitourinary, digestive, congenital, metabolic, mental and neurologic categories. Phenotype risk scores (PheRS) based on weighted aggregations of EHR phenotypes accurately predicted variant pathogenicity for at least 50% of pathogenic variants for 8/23 genes. We generated a catalog of PheRS for 7800 variants, including 5217 variants of uncertain significance, to provide empirical evidence of potential pathogenicity. This study highlights the potential of EHR data in genomic medicine.

The Hereditary Cancer Program at Vanderbilt-Ingram Cancer Center (VICC) was established in mid-2012 and provides cancer genetic services to patients and family members who are at risk for family cancer syndromes. During this time, the testing paradigm has markedly shifted from testing a small number of genes to a larger multi-gene set. HYPOTHESIS AND METHODS: We hypothesized that multi-gene testing would identify a higher rate of pathogenic mutations in breast cancer patients than the standard BRCA1/2 testing paradigm. To test this notion, we examined the records of 641 women with breast cancer seen in our clinic from July 2012 through Dec 2014 and tabulated the test outcome in women tested for BRCA1/2 only and women who had multi-gene panels. Patient characteristics were compared between the two groups. RESULTS: Excluding 17 (3%) women with a known familial mutation and the 127 (20%) women who did not proceed with testing, 497 women had usual Sanger BRCA1/2 (189; 38%) or a multi-gene NGS testing (308; 62%). 40 (13%) women were found to have a pathogenic mutation using the multi-gene panel compared to 13 (6%) women who had a restricted BRCA1/2 sequencing (P=0.035, Fishers Exact Test). The 13 women with Sanger BRCA1/2 were younger at diagnosis (40.6 vs 48 yrs) and more likely to have triple negative (TN) disease (38% vs 18%) compared to the 40 women diagnosed with multi-gene panels. TN disease was not confined to BRCA1 carriers, however, as 3 of 7 TN patients had a mutation in BRCA2, PALB2, and ATM, respectively. Thus, 29% (2/7) of our triple negative patients would not have been identified without multi-gene panels. In addition to BRCA1 (6; 15%) and BRCA2 (5; 12.5%), 6 women had mutations in ATM (15%), 7 in CHEK2 (17.5%), 6 in MUTYH (15%), 4 in PALB2 (10%), 2 in TP53 (5%), and 1 each in FANCC, PMS2, RAD51D and XRCC2 (2.5% each). 105 patients (35%) who did not have a deleterious mutation on a multi-gene panel were found to have one or more variants of uncertain significance (VUS) compared to 4 patients who underwent BRCA1/2 testing alone (4/189; 2%). There was a significant difference between providers when ordering hereditary cancer testing, with MD or NP ordering panel testing at a greater rate compared to Genetic Counselors (72% vs 53%; P< 0.0001). CONCLUSION: We have examined the outcomes of genetic tests for 497 women with breast cancer during a time of great change in the approach to testing. Our study supports the paradigm that multi-gene panels will identify additional pathogenic mutations in genes other than BRCA1/2, which could increase clinical efficiency and improve patient outcomes. However, our study also found a high VUS rate in this group of patients, which will require additional clinical time to track for potential changes in pathogenicity. Future studies will focus on potential differences in management for patients found to have alterations on multi-gene tests. Citation Format: Wiesner GL, Lewis S, Holt J, Morgan RH, Riddle DA, Trump SA, McReynolds K. The changing paradigm of hereditary cancer testing: Comparison of tests in 497 women with breast cancer evaluated at an NCI designated cancer center. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-06-01.

We studied the penetrance and clinical outcomes of seven breast cancer susceptibility genes (BRCA1, BRCA2, TP53, CHEK2, ATM, PALB2 and PTEN) in almost 25,000 participants unselected for personal or family history of breast cancer. We identified 420 participants with pathogenic or likely pathogenic variants, and 147 were women who did not previously know their genetic results. Out of these 147 women, 32 women were diagnosed with breast cancer at an average age of 52.8 years. Estimated penetrance by age 60 years ranged from 18-44%, depending on the gene. Within the first twelve months after genetic results disclosure, 42% of women had taken actions related to their genetic results and two new breast cancer cases were identified. Our study provides population-based penetrance estimates for the understudied genes, CHEK2, ATM, and PALB2, and highlights the importance of using unselected populations for penetrance studies. It also demonstrates the potential clinical impact of genetic testing to improve healthcare through early diagnosis and preventative screening.