SAN ANTONIO—Variants of uncertain significance (VUS) represent an array of gene mutations, many of them identified through BRCA gene and cancer risk gene panel testing. But they are “problematic for the clinical management of BRCA1/2 patients,” according to Fergus J. Couch PhD, of the Mayo Clinic in Rochester, MN. Dr. Couch spoke about VUS at the 2015 San Antonio Breast Cancer Symposium.
VUS findings can complicate risk assessments for patients and their family members, decisions about prophylactic surgery, and treatment options like PARP inhibitors, Dr. Couch explained.
Researchers have identified more than 3000 individual VUS, which represent up to 3% of all variants detected in the United States—and higher for some populations.
As gene panels proliferate, VUS classifications will likely increase, because younger labs have access to fewer family and pathology data with which they can be identified.
Efforts are underway to classify VUS and determine their clinical relevance and cancer-risk implications, Dr. Couch noted. Examples include the ENIGMA (Evidence-based Network for the Interpretation of Germline Mutant Alleles) consortium, an expert panel, ClinVar/ClinGen, and BRCA Challenge.
ENIGMA uses a quantitative model and multifactorial statistical-likelihood analysis to help assess the probability that a VUS represents a pathogenic or disease-associated variant. Factors used in the model include a bioinformatics “prior probability of pathogenicity” assessment of gene conservation across species and odds ratios from clinical or experimental study data, Dr. Couch noted.
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The “prior probability of pathogenicity” bioinformatics component of the model compares amino acid sequence variability across numerous animal species.
If the variant is a mutation in a sequence that has been highly conserved through deep evolutionary time across species, that mutation is likely to be disrupting a functionally important gene sequence, Dr Couch explained, because evolutionarily conserved sequences tend to play important biological functions.
- Couch FJ. Variants of uncertain significance. Oral presentation at: San Antonio Breast Cancer Symposium 2015; December 8, 2015; San Antonio, TX.