Large Panels Complicate Results Reporting for Breast Cancer Risk

Increasing the number of genes evaluated in individuals undergoing assessment for breast or ovarian cancer risk through large panels or whole exome sequencing (WES) does not increase the rate of molecular diagnosis, but rather, complicates reporting with a “substantial burden” of incidental and uncertain results, according to a study published May 5 in the American Journal of Human Genetics. The study also found clinical utility in the American College of Medical Genetics and Genomics (ACMG) variant-classification guidelines.

The plummeting cost of sequencing and identification of an increasing number of potential breast-cancer-susceptibility variants have driven interest in the clinical use of large, multi-gene panels (sometimes with 100-plus genes) and WES to assess genetic cancer risk. However, the expanded sets of genes quarried have varying levels of evidence to support their association with cancer susceptibility and the large gene sets complicate results reporting because of incidental findings.

Researchers from the SIMPLEXO (Simplifying Complex Exomes) consortium evaluated the ability of a variant-classification methodology based ACMG guidelines to define the rate of mutations and variants of uncertain significance (VUS) in 180 medically relevant genes in individuals who met guidelines for hereditary cancer risk evaluation. WES was performed in 404 individuals (from 253 families).

The researchers found 1,640 unique, non-silent exonic germline variants in 167 of the 180 genes. For genes with at least one variant identified, on average, 10 variants per gene were found. Individuals had on average 97 nonsynonymous variants and small insertion or deletion variants. Potentially clinically actionable variants, which included likely pathogenic or pathogenic calls, were 95 percent concordant with locus-specific databases (LSDB) and Clinvar, but absolute call concordance was lower for all genes, compared to those that were potentially actionable.

The vast majority of individuals tested (95 percent) had at least one variant of unknown significance (VUS), but the rate varied substantially from 12 percent for the well-established breast cancer susceptibility genes versus 78 percent when additional genes associated with autosomal-dominant (AD) cancer susceptibility were analyzed. VUS rates were also high for the non-cancer-associated genes (77 percent of families) and genes associated with autosomal-recessive cancer susceptibility (68 percent).

“The high concordance of variant calls with LSDBs and Clinvar suggests the clinical utility of variant classification based on ACMG guidelines coupled with expert review,” writes senior author Katherine Nathanson, M.D., from University of Pennsylvania in Philadelphia. “Our results strongly support the view that additional research studies are needed to resolve VUSs and understand the implications of incidental and/or unexpected results obtained from genetic testing for the assessment of cancer susceptibility. Our data do not support the use of medical exome or WES for evaluation of cancer susceptibility in individuals at high risk for breast and/or ovarian cancer at this time.”

Takeaway: Increasing the number of genes assayed for testing for breast and ovarian cancer susceptibility has minimal clinical impact and leads to increasing clinical complexity as a result of increased identification of VUS.