Classification of missense substitutions in the BRCA genes: A database dedicated to Ex-UVs

Abstract

Unclassified sequence variants (UV) arising from clinical mutation screening of cancer susceptibility genes present a frustrating issue to clinical genetics services and the patients that they serve. We created an open-access database holding missense substitutions from the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2. The main inclusion criterion is that each variant should have been assessed in a published work that used the Bayesian integrated evaluation of unclassified BRCA gene variants. Transfer of data on these substitutions from the original publications to our database afforded an opportunity to analyze the missense substitutions under a single model and to remove inconsistencies that arose during the evolution of the integrated evaluation over the last decade. This analysis also afforded the opportunity to re-classify these missense substitutions according to the recently published IARC 5-Class system. From an initial set of 248 missense substitutions, 31 were set aside due to non-negligible probability to interfere with splicing. Of the remaining substitutions, 28 fell into one of the two pathogenic classes (IARC Classes 4 or 5), 174 fell into one of the two non-pathogenic classes (IARC Classes 1 or 2), and 15 remain in IARC Class 3, “Uncertain”. The database is available at <http://brca.iarc.fr/LOVD>.

Clinicopathologic Features and Germline Sequence Variants in Young Patients (≤40 Years Old) With Pancreatic Ductal Adenocarcinoma

“…20 For BRCA1 and BRCA2, variants were classified using the database generated by Vallée et al, 21 accessed through the LOVD Web site (available at: http://brca.iarc.fr/LOVD).…”

BRCA1 R1699Q variant displaying ambiguous functional abrogation confers intermediate breast and ovarian cancer risk

“…Moreover, this quantitative assessment of risk has been linked to clinical management guidelines to provide a basis for standardised variant reporting, variant classification and management of families with such variants 2. The multifactorial likelihood methodology has been applied in multiple studies,1 3–15 with more than 200 BRCA1 or BRCA2 variants now classified using this approach 16. However, the multifactorial approach is designed to distinguish high-risk mutations from variants with no or little clinical significance, and it is likely that additional methods are required to detect and validate BRCA1 or BRCA2 rare variants associated with more modest risks than the average penetrance reported for classical mutations in these genes, that is, 65% risk of breast cancer and 39% risk of ovarian cancer to age 70 years for BRCA1 mutations, and 45% risk of breast cancer and 11% risk of ovarian cancer to age 70 years for BRCA2 mutations 17…”

Arvelige perifere nevropatier diagnostisert ved dypsekvensering

“…The outcomes of the analyses and observations described here may be integrated using Bayesian statistical inference in a method called the 'integrated evaluation' or 'multifactorial method' (Vallée et al, 2011). This is finding application to diseases including breast cancer and Lynch syndrome (Spurdle, 2010).…”