Dataset Information

Integration of functional assay data results provides strong evidence for classification of hundreds of BRCA1 variants of uncertain significance.

ABSTRACT:

Purpose

BRCA1 pathogenic variant heterozygotes are at a substantially increased risk for breast and ovarian cancer. The widespread uptake of testing has led to a significant increase in the detection of missense variants in BRCA1, the vast majority of which are variants of uncertain clinical significance (VUS), posing a challenge to genetic counseling. Here, we harness a wealth of functional data for thousands of variants to aid in variant classification.

Methods

We have collected, curated, and harmonized functional data for 2701 missense variants representing 24.5% of possible missense variants in BRCA1. Results were harmonized across studies by converting data into binary categorical variables (functional impact versus no functional impact). Using a panel of reference variants we identified a subset of assays with high sensitivity and specificity (?80%) and apply the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) variant interpretation guidelines to assign evidence criteria for classification.

Results

Integration of data from validated assays provided ACMG/AMP evidence criteria in favor of pathogenicity for 297 variants or against pathogenicity for 2058 representing 96.2% of current VUS functionally assessed. We also explore discordant results and identify limitations in the approach.

Conclusion

High quality functional data are available for BRCA1 missense variants and provide evidence for classification of 2355 VUS according to their pathogenicity.

SUBMITTER: Lyra PCM

PROVIDER: S-EPMC7862071 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Publications

Integration of functional assay data results provides strong evidence for classification of hundreds of BRCA1 variants of uncertain significance.

Lyra Paulo C M PCM Nepomuceno Thales C TC de Souza Marcele L M MLM Machado Géssica F GF Veloso Mariana F MF Henriques Taciane B TB Dos Santos Diandra Z DZ Ribeiro Iuly G IG Ribeiro Roberto S RS Rangel Leticia B A LBA Richardson Marcy M Iversen Edwin S ES Goldgar David D Couch Fergus J FJ Carvalho Marcelo A MA Monteiro Alvaro N A ANA

Genetics in medicine : official journal of the American College of Medical Genetics 20201022 2

<h4>Purpose</h4>BRCA1 pathogenic variant heterozygotes are at a substantially increased risk for breast and ovarian cancer. The widespread uptake of testing has led to a significant increase in the detection of missense variants in BRCA1, the vast majority of which are variants of uncertain clinical significance (VUS), posing a challenge to genetic counseling. Here, we harness a wealth of functional data for thousands of variants to aid in variant classification.<h4>Methods</h4>We have collected ...[more]

PMID: 33087888

Similar Datasets

Project description:Mutations in BRCA1 and BRCA2 are responsible for a large proportion of breast-ovarian cancer families. Protein-truncating mutations have been effectively used in the clinical management of familial breast cancer due to their deleterious impact on protein function. However, the majority of missense variants identified throughout the genes continue to pose an obstacle for predictive informative testing due to low frequency and lack of information on how they affect BRCA1/2 function. Phosphorylation of BRCA1 and BRCA2 play an important role in their function as regulators of DNA repair, transcription and cell cycle in response to DNA damage but whether missense variants of uncertain significance (VUS) are able to disrupt this important process is not known. Here we employed a novel approach using NetworKIN which predicts in vivo kinase-substrate relationship, and evolutionary conservation algorithms SIFT, PolyPhen and Align-GVGD. We evaluated whether 191 BRCA1 and 43 BRCA2 VUS from the Breast Cancer Information Core (BIC) database can functionally alter the consensus phosphorylation motifs and abolish kinase recognition and binding to sites known to be phosphorylated in vivo. Our results show that 13.09% (25/191) BRCA1 and 13.95% (6/43) BRCA2 VUS altered the phosphorylation of BRCA1 and BRCA2. We highlight six BRCA1 (K309T, S632N, S1143F, Q1144H, Q1281P, S1542C) and three BRCA2 (S196I, T207A, P3292L) VUS as potentially clinically significant. These occurred rarely (n<2 in BIC), mutated evolutionarily conserved residues and abolished kinase binding to motifs established in the literature involved in DNA repair, cell cycle regulation, transcription or response to DNA damage. Additionally in vivo phosphorylation sites identified via through-put methods are also affected by VUS and are attractive targets for studying their biological and functional significance. We propose that rare VUS affecting phosphorylation may be a novel and important mechanism for which BRCA1 and BRCA2 functions are disrupted in breast cancer.

Dataset Information

Integration of functional assay data results provides strong evidence for classification of hundreds of BRCA1 variants of uncertain significance.

Purpose

Methods

Results

Conclusion

Publications

Integration of functional assay data results provides strong evidence for classification of hundreds of BRCA1 variants of uncertain significance.

Similar Datasets

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