Mutational spectrum in a worldwide study of 29,700 families withBRCA1orBRCA2mutations

Abstract

The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease‐associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population‐specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad‐based oncogenetic testing in some populations.

BRCA2 loss‐of‐function germline mutations are associated with esophageal squamous cell carcinoma risk in Chinese

“…The prevalence and spectrum of BRCA2 mutations vary substantially in different geographical regions and ethnicities, which result in phenotypic variations . The pathogenic role and biological significance of K3326X in BRCA2 remain unclear and controversial in cancer.…”

BRCA1andBRCA2pathogenic sequence variants in women of African origin or ancestry

“…IFD was more common in BRCA1 SRAA (but this included very few PSVs), and PSV class was different between SRAA and non‐SRAA in BRCA2 . For BRCA1 , large deletions and duplications were not significantly different in frequency in CIMBA SRAA versus the previously reported CIMBA distribution (T. R. Rebbeck et al, ). There was also no significant difference for splice variants, PSV class, or lack of NMD with reinitiation, and marginally significant differences with missense PSVs, nonsense PSVs, no RNA, or reinitiation.…”

“…Knowledge of genetic risk is valuable because it can lead to the use of risk‐reducing salpingo‐oophorectomy or bilateral mastectomy, which significantly decrease breast and/or ovarian cancer risk and mortality BRCA1/2 PSV carriers (Domchek et al, ; Domchek et al, ; Domchek and Rebbeck, ; Domchek, Stopfer, and Rebbeck, ; Rebbeck, Kauff, and Domchek, ; T. R. Rebbeck et al, ; Rebbeck, Kauff, and Domchek, ). However, the vast majority of information about cancer risk and risk reduction has to date been conducted in Caucasian and Ashkenazi Jewish women (Rebbeck et al, ).…”

Germline variation in BRCA1/2 is highly ethnic‐specific: Evidence from over 30,000 Chinese hereditary breast and ovarian cancer patients

“…The variants were annotated using ANNOVAR with eight reference databases namely: RefGene, dbSNP (version 150), 1000genome, ESP6500, ExAC, ClinVar, InterVar and DBNSFP . Following BRCA databases were used for the comparative analysis: BIC (https://research.nhgri.nih.gov/bic/, accessed February 20, 2018), ClinVar(http://www.ncbi.nlm.nih.gov/clinvar/, accessed February 20, 2018), BRCA Exchange (http://brcaexchange.org, accessed February 20, 2018), ENIGMA (downloaded from BED database, http://brcaexchange.org, accessed February 20, 2018), BMD (http://www.arup.utah.edu/database/BRCA/Home/BRCA1_landing.php,http://www.arup.utah.edu/database/BRCA/Home/BRCA2_landing.php)(https://www.aruplab.com/topics/breast-cancer/brcadatabase, accessed February 20, 2018), LOVD (http://www.lovd.nl/3.0/home, accessed February 20, 2018) and CIMBA . The Chinese variants present in these databases were classified as known variants; those absent were classified as novel variants and deposited in ClinVar database (accession number nstd165).…”

“…Furthermore, it will determine whether the Caucasian‐based BRCA data is adequate to serve as a universal reference to determine BRCA status in non‐Caucasian populations around the world, or whether the ethnicity‐based BRCA mutation data should be developed instead. However, the answer remains elusive owing to the lack of BRCA data from most of the non‐Caucasian populations . For example, in the recently completed CIMBA study that collected BRCA data from 49 countries across six continents, the data available from any single, non‐Caucasian ethnic populations remain very limited .…”