Clinical mutation screening of the BRCA1 and BRCA2 breast and ovarian cancer predisposition genes (MIM#s 113705, 600185, respectively) for the presence of germline inactivating mutations is a widely used method for identifying individuals at elevated risk of breast and ovarian cancer. The criteria for genetic testing of these genes vary, but generally women with a significant family history of these cancers are offered testing. The following are possible outcomes of genetic testing:
Pathogenic mutations: Based on testing criteria, between 10% and 15% of all genetic tests yield known pathogenic mutations, often called “deleterious” mutations (See Definitions of Vocabulary) that truncate and/or inactivate BRCA1
and predispose to an elevated age-specific risk of breast and ovarian cancer. These are DNA variants that take the form of nonsense mutations, small out-of-frame insertion or deletion mutations, larger gene rearrangements and splicing alterations that all truncate or remove important domains of the BRCA proteins. In addition, certain missense substitutions are considered “pathogenic” because they inactivate protein function. These mutations can be confidently predicted to disrupt the function of the BRCA1
protein leading to increased risk of breast or ovarian cancer. Individuals who carry inherited pathogenic mutations in their DNA have, on average, substantially elevated age-dependent risks of breast and ovarian cancer compared to those without mutations in the general population. Women carrying pathogenic BRCA1
mutations have a 59% risk of breast cancer and a 34% risk of ovarian cancer by age 70, whereas women with BRCA2
pathogenic mutations have a 51% breast cancer and 11% ovarian cancer risk by age 80 (Antoniou, et al., 2008
). These risks may vary by population but are always significantly elevated over population risks. Importantly, individuals with BRCA1
mutations and their family members can benefit from risk assessment, enhanced cancer surveillance, risk-reducing prophylactic mastectomy and oophorectomy, and counseling. Specifically, those carrying pathogenic mutations are known to be at substantially elevated risk of cancer, whereas individuals from the same families who do not carry the pathogenic mutation benefit from the knowledge that they are not at increased risk of cancer.
Not pathogenic or low clinical significance (LCS) variants: A further 80% of tests either fail to identify alterations in the BRCA1 and BRCA2 genes or identify variants that are considered to be “not pathogenic”, often termed “neutral”, or of “low clinical significance” low clinical significance” (See Sources of Data). This group of variants includes common polymorphisms, seen in greater than 1% of alleles in the general population, and rare variants that display little or no association with breast cancer risk in families. These variants are predicted or have been shown to have no significant influence on the normal function of the BRCA1 or BRCA2 proteins.
ariants of u
ignificance (VUS): In many countries as many as 30% to 50% of variants identified during BRCA1 and BRCA2 gene testing are Variants of Uncertain Significance (VUS), also referred to as unclassified variants (UVs) (Hofstra, et al., 2008
). In the USA these variants may only account for 5% to 10% of alterations because of ongoing classification efforts by Myriad Genetics Laboratories Inc. VUS are mainly missense substitutions that result in single amino acid changes, but also include in-frame small deletions or insertions that change only small numbers of amino acids, silent coding alterations that may influence splicing or translation, or intronic changes of unknown influence on gene splicing. These alterations have unknown functional effects on BRCA1
and cannot at this time be classified as either “Pathogenic” or “Not Pathogenic/low clinical significance”. As a result individuals found to carry these variants in their DNA and members of their families cannot benefit from risk assessment measures offered to members of families known to carry BRCA1
deleterious mutations. Unfortunately, even though individual VUS are rare, the finding of a VUS is not a rare event. At present, there are hundreds of unique VUS recorded in the BRCA genes (Breast Cancer Information Core Database: http://research.nhgri.nih.gov/bic/