|
|
|
|
|
|
|
|
abstract
Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer
Author information
Abstract
Sequencing tests assaying panels of genes or whole exomes are widely available for cancer
risk evaluation. However, methods for classification of variants
resulting from this testing are not well studied. We evaluated the
ability of a variant-classification methodology based on American
College of Medical Genetics and Genomics (ACMG) guidelines to define the
rate of mutations and variants of uncertain significance (VUS) in 180
medically relevant genes, including all ACMG-designated reportable cancer and non-cancer-associated genes, in individuals who met guidelines for hereditary cancer
risk evaluation. We performed whole-exome sequencing in 404 individuals
in 253 families and classified 1,640 variants. Potentially clinically
actionable (likely pathogenic [LP] or pathogenic [P]) versus
nonactionable (VUS, likely benign, or benign) calls were 95% concordant
with locus-specific databases and Clinvar. LP or P mutations were
identified in 12 of 25 breast cancer
susceptibility genes in 26 families without identified BRCA1/2
mutations (11%). Evaluation of 84 additional genes associated with
autosomal-dominant cancer
susceptibility identified LP or P mutations in only two additional
families (0.8%). However, individuals from 10 of 253 families (3.9%) had
incidental LP or P mutations in 32 non-cancer-associated
genes, and 9% of individuals were monoallelic carriers of a rare LP or P
mutation in 39 genes associated with autosomal-recessive cancer
susceptibility. Furthermore, 95% of individuals had at least one VUS.
In summary, these data support the clinical utility of ACMG
variant-classification guidelines. Additionally, evaluation of extended
panels of cancer-associated genes in breast/ovarian cancer families leads to only an incremental clinical benefit but substantially increases the complexity of the results.
2016 The American Society of Human Genetics
2016 The American Society of Human Genetics
0 comments :
Post a Comment
Your comments?
Note: Only a member of this blog may post a comment.