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Cancers 2019, 11(4), 522; https://doi.org/10.3390/cancers11040522

Germline Missense Variants in BRCA1: New Trends and Challenges for Clinical Annotation

Cancer Epidemiology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
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Received: 7 February 2019 / Revised: 13 March 2019 / Accepted: 30 March 2019 / Published: 12 April 2019
(This article belongs to the Special Issue BRCA Mutations and Cancer)
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Abstract

Genetic testing allows for the identification of germline DNA variations, which are associated with a significant increase in the risk of developing breast cancer (BC) and ovarian cancer (OC). Detection of a BRCA1 or BRCA2 pathogenic variant triggers several clinical management actions, which may include increased surveillance and prophylactic surgery for healthy carriers or treatment with the PARP inhibitor therapy for carriers diagnosed with cancer. Thus, standardized validated criteria for the annotation of BRCA1 and BRCA2 variants according to their pathogenicity are necessary to support clinical decision-making and ensure improved outcomes. Upon detection, variants whose pathogenicity can be inferred by the genetic code are typically classified as pathogenic, likely pathogenic, likely benign, or benign. Variants whose impact on function cannot be directly inferred by the genetic code are labeled as variants of uncertain clinical significance (VUS) and are evaluated by multifactorial likelihood models that use personal and family history of cancer, segregation data, prediction tools, and co-occurrence with a pathogenic BRCA variant. Missense variants, coding alterations that replace a single amino acid residue with another, are a class of variants for which determination of clinical relevance is particularly challenging. Here, we discuss current issues in the missense variant classification by following a typical life cycle of a BRCA1 missense variant through detection, annotation and information dissemination. Advances in massively parallel sequencing have led to a substantial increase in VUS findings. Although the comprehensive assessment and classification of missense variants according to their pathogenicity remains the bottleneck, new developments in functional analysis, high throughput assays, data sharing, and statistical models are rapidly changing this scenario. View Full-Text
Keywords: BRCA1; variants of uncertain clinical significance; VUS; germline variants; hereditary breast and ovarian cancer; breast cancer; genetic testing; ovarian cancer; variant classification; clinical annotation BRCA1; variants of uncertain clinical significance; VUS; germline variants; hereditary breast and ovarian cancer; breast cancer; genetic testing; ovarian cancer; variant classification; clinical annotation
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Golubeva, V.A.; Nepomuceno, T.C.; Monteiro, A.N.A. Germline Missense Variants in BRCA1: New Trends and Challenges for Clinical Annotation. Cancers 2019, 11, 522.

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