Additional file 2: Figure S1. of Characterization of BRCA1 and BRCA2 variants in multi-ethnic Asian cohort from a Malaysian case-control study

Association of BRCA1 and BRCA2 variants with breast cancer risk in all breast cancer cases and healthy controls. The forest plot illustrates the association of BRCA1 and BRCA2 variants with breast cancer risk in all breast cancer cases and healthy controls. Figure S2. Association of variants with breast cancer risk in ethnicity subgroups: (a) BRCA1 and (b) BRCA2. The forest plot illustrates the association of BRCA1 and BRCA2 variants with breast cancer risk in certain ethnicity subgroups that can be analyzed. (DOCX 145 kb

Additional file 1: Table S1a. of Characterization of BRCA1 and BRCA2 variants in multi-ethnic Asian cohort from a Malaysian case-control study

BRCA1 variants included in genotyping assay design. A total of 23 BRCA1 variants were included in the genotyping assay. Of these, two variants were excluded due to genotyping call rate <95%. Table S1b. BRCA2 variants included in genotyping assay design. A total of 44 BRCA2 variants were included in the genotyping assay. Of these, two variants were excluded due to genotyping call rate <95%. Table S2. Characteristics of Malaysian breast cancer cases and healthy controls in ethnicity subgroups: (a) Chinese, (b) Malay and (c) Indian. There was no difference in age for cases and controls for Chinese and Indian women, but healthy women were on average 2 years older than the cases for Malay women. Table S3a. Frequency of BRCA1 variants detected in ethnicity subgroups. The table describes the frequency of BRCA1 variants detected in Chinese, Malay and Indian women. Table S3b. Frequency of BRCA2 variants detected in ethnicity subgroups. The table describes the frequency of BRCA2 variants detected in Chinese, Malay and Indian women. (DOCX 195 kb

Inherited mutations in BRCA1 and BRCA2 in an unselected multiethnic cohort of Asian patients with breast cancer and healthy controls from Malaysia.

BACKGROUND: Genetic testing for BRCA1 and BRCA2 is offered typically to selected women based on age of onset and family history of cancer. However, current internationally accepted genetic testing referral guidelines are built mostly on data from cancer genetics clinics in women of European descent. To evaluate the appropriateness of such guidelines in Asians, we have determined the prevalence of germ line variants in an unselected cohort of Asian patients with breast cancer and healthy controls. METHODS: Germ line DNA from a hospital-based study of 2575 unselected patients with breast cancer and 2809 healthy controls were subjected to amplicon-based targeted sequencing of exonic and proximal splice site junction regions of BRCA1 and BRCA2 using the Fluidigm Access Array system, with sequencing conducted on a Illumina HiSeq2500 platform. Variant calling was performed with GATK UnifiedGenotyper and were validated by Sanger sequencing. RESULTS: Fifty-five (2.1%) BRCA1 and 66 (2.6%) BRCA2 deleterious mutations were identified among patients with breast cancer and five (0.18%) BRCA1 and six (0.21%) BRCA2 mutations among controls. One thousand one hundred and eighty-six (46%) patients and 97 (80%) carriers fulfilled the National Comprehensive Cancer Network guidelines for genetic testing. CONCLUSION: Five per cent of unselected Asian patients with breast cancer carry deleterious variants in BRCA1 or BRCA2. While current referral guidelines identified the majority of carriers, one in two patients would be referred for genetic services. Given that such services are largely unavailable in majority of low-resource settings in Asia, our study highlights the need for more efficient guidelines to identify at-risk individuals in Asia

BRCA2 Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer

Breast cancer risks conferred by many germline missense variants in the BRCA1 and BRCA2 genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk were investigated through a breast cancer case-control study using genotyping data from 38 studies of predominantly European ancestry (41,890 cases and 41,607 controls) and nine studies of Asian ancestry (6,269 cases and 6,624 controls). The BRCA2 c.9104A&gt;C, p.Tyr3035Ser (OR = 2.52; P = 0.04), and BRCA1 c.5096G&gt;A, p.Arg1699Gln (OR = 4.29; P = 0.009) variant were associated with moderately increased risks of breast cancer among Europeans, whereas BRCA2 c.7522G&gt;A, p.Gly2508Ser (OR = 2.68; P = 0.004), and c.8187G&gt;T, p.Lys2729Asn (OR = 1.4; P = 0.004) were associated with moderate and low risks of breast cancer among Asians. Functional characterization of the BRCA2 variants using four quantitative assays showed reduced BRCA2 activity for p.Tyr3035Ser compared with wild-type. Overall, our results show how BRCA2 missense variants that influence protein function can confer clinically relevant, moderately increased risks of breast cancer, with potential implications for risk management guidelines in women with these specific variants. Cancer Res; 77(11); 2789-99. ©2017 AACR

BRCA2 Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer

CANCER RESEARCH77112789-2799CNRE