Variants of uncertain significance
Germlinedeleterious mutations in the BRCA1/BRCA2 genes are associated with an approximately 60% lifetime risk of breast cancer and a 15% to 40% lifetime risk of ovarian cancer. There are no definitive functional tests for BRCA1 or BRCA2; therefore, the classification of nucleotide changes to predict their functional impact as deleterious or benign relies on imperfect data. The majority of accepted deleterious mutations result in protein truncation and/or loss of important functional domains. However, 10% to 15% of all individuals undergoing genetic testing with full sequencing of BRCA1 and BRCA2 will not have a clearly deleterious mutation detected but will have a variant of uncertain (or unknown) significance (VUS). Variants of uncertain significance may cause substantial challenges in counseling, particularly in terms of cancer risk estimates and risk management. Clinical management of such patients needs to be highly individualized and must take into consideration factors such as the patient's personal and family cancer history, in addition to sources of information to help characterize the VUS as benign or deleterious. Thus an improved classification and reporting system may be of clinical utility.
African Americans appear to have a higher rate of VUS. A comprehensive analysis examined the results of 7,461 consecutive full gene sequence analyses performed by Myriad Genetic Laboratories, Inc., over a 3-year period. Among subjects who had no clearly deleterious mutation, 13% had VUS defined as "missense mutations and mutations that occur in analyzed intronic regions whose clinical significance has not yet been determined, chain-terminating mutations that truncate BRCA1 and BRCA2 distal to amino acid positions 1853 and 3308, respectively, and mutations that eliminate the normal stop codons for these proteins." The classification of a sequence variant as a VUS is a moving target. An additional 6.8% of subjects with no clear deleterious mutations had sequence alterations that were once considered VUS, but were reclassified as a polymorphism, or occasionally as a deleterious mutation. In a 2009 study of data from Myriad, 16.5% of individuals of African ancestry had VUS, the highest rate among all ethnicities. Over time, the rate of changes classified as VUS has decreased in all ethnicities, largely due to improved mutation classification algorithms. VUS continue to be reclassified as additional information is accumulated. Such information may impact the continuing care of affected individuals.
A number of methods for discriminating deleterious from neutral VUS exist and others are in development [30,31,32,33] including integrated methods (see below). Interpretation of VUS is greatly aided by efforts to track VUS in the family to determine if there is cosegregation of the VUS with the cancer in the family. In general, a VUS observed in individuals who also have a deleterious mutation, especially when the same VUS has been identified in conjunction with different deleterious mutations, is less likely to be in itself deleterious, although there are rare exceptions. As an adjunct to the clinical information, models to interpret VUS have been developed, based on sequence conservation, biochemical properties of amino acid changes,[30,35,36,37,38,39] incorporation of information on pathologic characteristics of BRCA1- and BRCA2-related tumors (e.g., BRCA1-related breast cancers are usually estrogen receptor [ER] negative), and functional studies to measure the influence of specific sequence variations on the activity of BRCA1 or BRCA2 proteins.[41,42] When attempting to interpret a VUS, all available information should be examined.