Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer

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.

Clinotator: analyzing ClinVar variation reports to prioritize reclassification efforts

“…Most shifts occurred between the overlap categories and their immediate neighbors, likely resulting from the altered definition of the overlap category. Both of these results support previous research showing a fairly high general concordance in ClinVar 18, 37, 38 .…”

Investigation of clinically relevant germline variants detected by next-generation sequencing in patients with childhood cancer: a review of the literature

“…For example, two studies16 17 reported heterozygous germline variants in ATM , responsible for the autosomal recessive syndrome ataxia telangiectasia, with an associated high risk of developing haematological malignancies 27. As all individuals are expected to carry a variant associated with a recessive condition,29 the clinical significance of monoallelic variants in autosomal recessive genes in cancer predisposition is thought to be minimal in children 30. Lack of genotype–phenotype concordance was also demonstrated for germline variants in autosomal dominant cancer predisposition genes not previously associated with the specific childhood cancer diagnosed in the patient.…”

A framework for exhaustively mapping functional missense variants

“…Unfortunately, we have only a limited ability to interpret personal genomes, each carrying 100–400 rare missense variants (The 1000 Genomes Project Consortium, 2015) of which many must currently be classified as “variants of uncertain significance” (VUS). For example, gene panel sequencing aimed at identifying germline cancer risk variants in families yielded VUS for the majority of missense variants (Maxwell et al , 2016). Functional variants can be predicted, but when high precision is required, computational tools (Adzhubei et al , 2010; Choi et al , 2012) detect only one‐third as many pathogenic variants as experimental assays (Sun et al , 2016).…”