1. Clinical Evaluation of a Multiple-Gene Sequencing Panel for Hereditary Cancer Risk Assessment Volume 32, Number 19, July. 1, 2014, from J Clin Oncol Chen Xinyi October 29,2015

2. BACKGROUND The BRCAs account for only about 25% of breast cancers with a hereditary component; Now unmasked dozens of other genes associated with breast cancer; Whether and how?

3. INTRODUCTION Sam Kean Science 2014.03

4. QUESTION How many and which genes to sequence? Whether results are sufficiently understood to guide intervention? How best to counsel patients about variants of low or moderate penetrance?

5. GENE SELECTED Reported breast cancer association Associated with other cancer syndromes DNA repair pathways Rendering a breast cancer–risk association plausible

7. Participant Accrual 198 were randomly selected From 654 research samples for study participation; 174 breast cancer ； 57 carried a BRCA1/2 mutation ； Participants were representative

8. RESULT Pathogenic variants in BRCA1/2:57 Pathogenic variants in other genes:16 （ 11.4%; 95% CI, 7.0% to 17.7%) VUS Variants of Uncertain Significance:428

9. RESULT

10. ATM (2 women), BLM (1 woman), CDH1 (1 woman), CDKN2A (1 woman), MLH1(1 woman), MUTYH(1 women), NBN(2 women), PRSS1(1 woman), SLX4 (2 women).

11. VUS Variants of Uncertain Significance A total of 428 VUS were identified in 39 genes among 175 participants. Per participant, the average number of VUS across all genes was 2.1

12. RESULT Studies of multigene panel for hereditary cancers ReferenceNSubjectsPanel genes 1 Cancer 121, 25-33 (2015)2158BC referred for BRCA gene testing25 2 Genet Med 16, 830-837 (2014)2079hereditary cancer14-22 3 J Clin Oncol 33, 304-311 (2015)1824TNBC17 4 J Mol Diagn 17, 533-544 (2015)1105HBOC risk assessment under NCCN guideline29 5 JAMA Oncol (2015)1046non-BRCA HBOC 29 、 25 6 Eur J Hum Genet 22, 1305-1313 (2014)93559 BRCA carriers+874 high-risk31 7 Gynecol Oncol 137, 86-92 (2015)911BC/OC21 8 J Clin Oncol 33, 2015 (suppl; abstr 1511)810non-BRCA BC with high-risk features20 9 Proc Natl Acad Sci U S A 108, 18032-18037 (2011)360primary ovarian, peritoneal, or fallopian tube carcinoma21 10 Ann Surg Oncol 22, 3282-3288 (2015)337 629 underwent limited BRCA1/2 testing and 337 patients underwent panel testing 5-43 11 Genet Med 17, 630-638 (2015)278non-BRCA BC with early-onset22 12 J Clin Oncol 32, 2001-2009 (2014)231174 BC+57 BRCA carriers42 13 FEBS J 282, 3424-3437 (2015)104non-BRCA BC312 1 Gastroenterology 149, 604-613 e620 (2015)1260clinical genetic testing for Lynch syndrome25 2 Gastroenterology 148, 556-564 (2015)708pancreatic cancers13 3 J Clin Oncol 33, 426-432 (2015)626early-onset familial CRC5