Combined annotation‐dependent depletion score for BRCA1/2 variants in patients with breast and/or ovarian cancer

Abstract

Utility of combined annotation‐dependent depletion (CADD) score was recently reported to rank pathogenicity as C‐scores ranging 1‐99 for both confirmed deleterious mutation. Using C‐scores for BRCA1/2 variants, we tried to constitute the classification system for variant of uncertain significance (VUS), which had been a major problem of genetic testing for hereditary breast and/or ovarian cancer. We analyzed BRCA1/2 genes for 283 patients with breast and/or ovarian cancer. The deleterious mutation and missesne mutations, minor variant, and wild type of BRCA1 and ‐2 were 5, 27, 251 and 15, 85, 183, respectively. Meanwhile, the variants with C‐score ≥10 were involved in 19/283 (6.7%) in BRCA1 and 34/283 (12%) in BRCA2. All deleterious mutations were included in this group. Frequency of personal history and family history of ovarian cancer were significantly high, and frequency of serous adenocarcinoma of ovary and triple negative breast cancer was relatively high in the group with deleterious mutations. Similar findings were seen in patients with variants of C‐score ≥10. According to the C‐score and population frequency, we could define VUS for 11 patients out of 283 patients (3.9 CADD is useful to classify the variant of BRCA1/2 and selecting the patient who needs further segregation studies.

Germline Genetic Findings Which May Impact Therapeutic Decisions in Families with a Presumed Predisposition for Hereditary Breast and Ovarian Cancer

“…Hence, another goal of this work was to characterise the spectrum of rare variants, other than pathogenic ones, which may lead to an increased risk for breast/ovarian cancer predisposition. The CADD tool seems very useful for identifying causal mutations with a high score of pathogenicity [34,35]. Moreover, it offers a practical and unbiased approach for estimating the pathogenicity of human genetic variants by integrating many diverse annotations into a single, quantitative score [35].…”

“…In practice, the CADD score alone could not be used for variant classification, but the algorithm might be useful for prioritising variants for further functional and segregation studies [35].…”

“…In the CADD method, the scaled-C-scores are related with the top-ranked pathogenicity: to CADD-Score-10 you are in the top 10% of the disrupting mutations, to CADD-Score-20, top 1%, CADD-Score-25, top 0.5% and to CADD-Score-30, 0.1%. CADD integrates diverse annotations into a single score by contrasting variants that survived natural selection with simulated mutations [35,52,53]. We considered variants with a CADD-score of >25 as possibly pathogenic (top 0.5% of disrupting variants).…”

Predicting Functional Effects of Synonymous Variants: A Systematic Review and Perspectives

“…CADD and DANN training data, for example, contains simulated human variants, appearing after human-chimpanzee divergence, labelled as the effect group (depleted by natural selection) and observed fixed or nearly fixed derived alleles as neutral (Kircher et al, 2014; Quang et al, 2014). Note although simulated variants are likely enriched in deleterious variants, and CADD scores have been shown useful in prioritizing variants in clinical settings (Amendola et al, 2015; Nakagomi et al, 2018; Van Der Velde et al, 2015), it is difficult to directly link the CADD predictions to pathogenicity (Kircher et al, 2014).…”

A Functional Analysis of the Unclassified Pro2767Ser BRCA2 Variant Reveals Its Potential Pathogenicity that Acts by Hampering DNA Binding and Homology-Mediated DNA Repair

“…Indeed, the correct interpretation of the significance of the BRCA1 and BRCA2 variants is crucial for genetic counseling and for the clinical management of HBOC patients and their relatives [6,7,8]. Therefore, much effort is being made to determine the role of BRCA1 and BRCA2 VUSs and of novel variants [9,10,11,12].…”