Preprint Review Version 1 This version is not peer-reviewed

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

Version 1 : Received: 7 February 2019 / Approved: 11 February 2019 / Online: 11 February 2019 (16:12:03 CET)

How to cite: Golubeva, V.; Nepomuceno, T.; Monteiro, A. Germline Missense Variants in BRCA1: New Trends and Challenges for Clinical Annotation. Preprints 2019, 2019020090 (doi: 10.20944/preprints201902.0090.v1). Golubeva, V.; Nepomuceno, T.; Monteiro, A. Germline Missense Variants in BRCA1: New Trends and Challenges for Clinical Annotation. Preprints 2019, 2019020090 (doi: 10.20944/preprints201902.0090.v1).

Abstract

Genetic testing allows for identification of germline DNA variations which are associated with a significant increase in risk of developing breast and ovarian cancer. 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 PARP inhibitor therapy for carriers diagnosed with cancer. Thus, standardized validated criteria for 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 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 comprehensive assessment and classification of missense variants according to their pathogenicity remains the bottle neck, new developments in functional analysis, high throughput assays, data sharing, and statistical models are rapidly changing this scenario.

Subject Areas

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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