e13684 Background: Pathogenic variants in cancer predisposition genes BRCA1/2 confer susceptibility to breast and ovarian cancer and well-studied. But the characteristics of BRCA in other cancers is unknown, we identified and characterized BRCA germline variants in a large pan-cancer in China. Methods: NGS was performed on genomic DNA from 29,676 pan-cancer patients. Large fragment deletions were all verified by QPCR. We integrated guidelines of ACMG/AMP, ENIGMA and China expert consensus. Based on the in-house system, variants were interpreted one-by-one and classified into 5 grades: Benign (B), Likely Benign(LB), Variant of Uncertain significance(VUS), Likely pathogenic (LP), Pathogenic (P). Results: Among 29,676 patients, 300 BRCA1 mutations and 440 BRCA2 mutations were detected in our study. The proportion among P/LP/VUS/LB/B were 36.1%, 11.6%, 36.6%, 11.1% and 4.6%. Consistent with previous reports, the mutations spread around the whole genes. Missense and frameshift were most common types in BRCA1 (40%, 25.3%) and BRCA2 (42.3%, 29.3%). 192(25.9%) mutations were not reported in any of the databases. Among these newly reported mutations, 32 (16.7%) were classified as P, 62 (32.3%) LP and 98 (51%) VUS. Totally, 522 (1.8%) patients were identified with P/LP BRCA1/2 mutations. No founder mutations in Chinese population were defined, but BRCA1 5470_5477delATTGGGCA (I1824Dfs*3) and BRCA2 3109C > T (Q1037*) had the highest prevalence indicating the common P/LP mutations in Chinese. On the whole, BRCA-associated hereditary cancer harbored higher P/LP percent than other cancer types (11.1% vs 0.7%). Different distribution and percent were observed in BRCA1 and BRCA2, the P/LP mutations were found in double primary cancers of breast and ovary (76.9% vs 38.5%), followed by ovarian cancer (15.5% vs 6.3%), breast cancer(3.8% vs 4.0%), endometrial cancer(1.6% vs 2.4%), prostatic cancer(1.3% vs 1.9%), pancreatic cancer (0.3% vs 1.8%), biliary tract tumor (0% vs 1%), thyroid cancer (0% vs 0.9%), NSCLC(0.2% vs 0.5%) and colorectal cancer(0.08% vs 0.4%). Except for SNV/Indels, large range heterozygous deletions were found in 9 patients, including 4 (0.6%) OC, 4 (0.2%) BC and 1 NSCLC, almost all interfering with BRCA1. Conclusions: This analysis depicted a comprehensive landscape of germline BRCA1/2 variants in Chinese pan-cancer. Besides breast and ovarian cancer, lots of other cancers also harbor BRCA germline mutation, retrospective family history and hereditary cancer risk assessment needs further study.
Genetic testing in Poland and Ukraine: should comprehensive germline testing of BRCA1 and BRCA2 be recommended for women with breast and ovarian cancer?
