Assessment of blind predictions of the clinical significance of BRCA1 and BRCA2 variants.
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ABSTRACT:
SUBMITTER: Cline MS
PROVIDER: S-EPMC6744348 | biostudies-literature | 2019 Sep
REPOSITORIES: biostudies-literature
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Assessment of blind predictions of the clinical significance of BRCA1 and BRCA2 variants.
Cline Melissa S MS Babbi Giulia G Bonache Sandra S Cao Yue Y Casadio Rita R de la Cruz Xavier X Díez Orland O Gutiérrez-Enríquez Sara S Katsonis Panagiotis P Lai Carmen C Lichtarge Olivier O Martelli Pier L PL Mishne Gilad G Moles-Fernández Alejandro A Montalban Gemma G Mooney Sean D SD O'Conner Robert R Ootes Lars L Özkan Selen S Padilla Natalia N Pagel Kymberleigh A KA Pejaver Vikas V Radivojac Predrag P Riera Casandra C Savojardo Castrense C Shen Yang Y Sun Yuanfei Y Topper Scott S Parsons Michael T MT Spurdle Amanda B AB Goldgar David E DE
Human mutation 20190823 9
Testing for variation in BRCA1 and BRCA2 (commonly referred to as BRCA1/2), has emerged as a standard clinical practice and is helping countless women better understand and manage their heritable risk of breast and ovarian cancer. Yet the increased rate of BRCA1/2 testing has led to an increasing number of Variants of Uncertain Significance (VUS), and the rate of VUS discovery currently outpaces the rate of clinical variant interpretation. Computational prediction is a key component of the varia ...[more]
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Project description:Current evidence suggests that the genetic risk of breast cancer may be caused primarily by rare variants. However, while classification of protein-truncating mutations as deleterious is relatively straightforward, distinguishing as deleterious or neutral the large number of rare missense variants is a difficult on-going task. In this article, we present one approach to this problem, hierarchical statistical modeling of data observed in a case-control study of contralateral breast cancer (CBC) in which all the participants were genotyped for variants in BRCA1 and BRCA2. Hierarchical modeling permits leverage of information from observed correlations of characteristics of groups of variants with case-control status to infer with greater precision the risks of individual rare variants. A total of 181 distinct rare missense variants were identified among the 705 cases with CBC and the 1,398 controls with unilateral breast cancer. The model identified three bioinformatic hierarchical covariates, align-GV, align-GD, and SIFT scores, each of which was modestly associated with risk. Collectively, the 11 variants that were classified as adverse on the basis of all the three bioinformatic predictors demonstrated a stronger risk signal. This group included five of six missense variants that were classified as deleterious at the outset by conventional criteria. The remaining six variants can be considered as plausibly deleterious, and deserving of further investigation (BRCA1 R866C; BRCA2 G1529R, D2665G, W2626C, E2663V, and R3052W). Hierarchical modeling is a strategy that has promise for interpreting the evidence from future association studies that involve sequencing of known or suspected cancer genes.
| S-EPMC3111904 | biostudies-literature
Project description:The influence of BRCA1/2 variants of uncertain significance (VUSs) on the cancer risk and their association with the response to treatment is uncertain. The aim of the present study was to evaluate the role of BRCA VUS in patients with breast cancer. A total of two cases of breast cancer patients with the BRCA VUS were described. The complete coding sequence of BRCA1/2 genes was analyzed from the genomic DNA material by next generation sequencing on the Ion Torrent platform. The presence of c.3454G>A (p.Asp1152Asn) VUS in the BRCA1 gene was reported in a 64-year-old woman with invasive breast carcinoma. The characteristics of the breast tumors were the following: moderately differentiated-intermediate grade (NG-2 G-2), HER2 (+), estrogen receptor (ER) (+++), progesterone receptor (PR) (+++), luminal A subtype and pT2 N1a Mx. The second detected VUS was the c.2374T>C (p.Tyr792His) variant in the BRCA2 gene. This variant was reported in a 33-year-old woman who was diagnosed with right breast cancer (cT2N1M0). The invasive breast carcinoma was characterized as follows: NG-2 G-2, ER (+++), PR (+++), Ki-67 10%, HER2 (+++) and luminal B subtype. The data demonstrated that patients with VUSs should be managed based on their family history of cancer and clinicopathological characteristics. The clinical significance of the VUS in BRCA1/2 may change over time and reclassification of the variant to 'pathogenic' or 'benign' should be undertaken. Patients with VUS should be followed up regularly.
| S-EPMC8447178 | biostudies-literature
Project description:BACKGROUND:Increasing use of BRCA1/2 testing for tailoring cancer treatment and extension of testing to tumour tissue for somatic mutation is moving BRCA1/2 mutation screening from a primarily prevention arena delivered by specialist genetic services into mainstream oncology practice. A considerable number of gene tests will identify rare variants where clinical significance cannot be inferred from sequence information alone. The proportion of variants of uncertain clinical significance (VUS) is likely to grow with lower thresholds for testing and laboratory providers with less experience of BRCA. Most VUS will not be associated with a high risk of cancer but a misinterpreted VUS has the potential to lead to mismanagement of both the patient and their relatives. DESIGN:Members of the Clinical Working Group of ENIGMA (Evidence-based Network for the Interpretation of Germline Mutant Alleles) global consortium (www.enigmaconsortium.org) observed wide variation in practices in reporting, disclosure and clinical management of patients with a VUS. Examples from current clinical practice are presented and discussed to illustrate potential pitfalls, explore factors contributing to misinterpretation, and propose approaches to improving clarity. RESULTS AND CONCLUSION:Clinicians, patients and their relatives would all benefit from an improved level of genetic literacy. Genetic laboratories working with clinical geneticists need to agree on a clinically clear and uniform format for reporting BRCA test results to non-geneticists. An international consortium of experts, collecting and integrating all available lines of evidence and classifying variants according to an internationally recognized system, will facilitate reclassification of variants for clinical use.
| S-EPMC5006185 | biostudies-literature
Project description:Many sequence variants in predisposition genes are of uncertain clinical significance, and classification of these variants into high- or low-risk categories is an important problem in clinical genetics. Classification of such variants can be performed by direct epidemiological observations, including cosegregation with disease in families and degree of family history of the disease, or by indirect measures, including amino acid conservation, severity of amino acid change, and evidence from functional assays. In this study, we have developed an approach to the synthesis of such evidence in a multifactorial likelihood-ratio model. We applied this model to the analysis of three unclassified variants in BRCA1 and three in BRCA2. The evidence strongly suggests that two variants (C1787S in BRCA1 and D2723H in BRCA2) are deleterious, three (R841W in BRCA1 and Y42C and P655R in BRCA2) are neutral, and one (R1699Q in BRCA1) remains of uncertain significance. These results provide a demonstration of the utility of the model.
| S-EPMC1182042 | biostudies-literature
Project description:Mutation screening of the breast and ovarian cancer-predisposition genes BRCA1 and BRCA2 is becoming an increasingly important part of clinical practice. Classification of rare nontruncating sequence variants in these genes is problematic, because it is not known whether these subtle changes alter function sufficiently to predispose cells to cancer development. Using data from the Myriad Genetic Laboratories database of nearly 70,000 full-sequence tests, we assessed the clinical significance of 1,433 sequence variants of unknown significance (VUSs) in the BRCA genes. Three independent measures were employed in the assessment: co-occurrence in trans of a VUS with known deleterious mutations; detailed analysis, by logistic regression, of personal and family history of cancer in VUS-carrying probands; and, in a subset of probands, an analysis of cosegregation with disease in pedigrees. For each of these factors, a likelihood ratio was computed under the hypothesis that the VUSs were equivalent to an "average" deleterious mutation, compared with neutral, with respect to risk. The likelihood ratios derived from each component were combined to provide an overall assessment for each VUS. A total of 133 VUSs had odds of at least 100 : 1 in favor of neutrality with respect to risk, whereas 43 had odds of at least 20 : 1 in favor of being deleterious. VUSs with evidence in favor of causality were those that were predicted to affect splicing, fell at positions that are highly conserved among BRCA orthologs, and were more likely to be located in specific domains of the proteins. In addition to their utility for improved genetics counseling of patients and their families, the global assessment reported here will be invaluable for validation of functional assays, structural models, and in silico analyses.
| S-EPMC2265654 | biostudies-literature
Project description:BACKGROUND:Deleterious variants in the tumour suppressor BRCA1 are known to cause hereditary breast and ovarian cancer syndrome (HBOC). Missense variants in BRCA1 pose a challenge in clinical care, as their effect on protein functionality often remains unknown. Many of the pathogenic missense variants found in BRCA1 are located in the BRCA1 C-terminal (BRCT) domains, domains that are known to be vital for key functions such as homologous recombination repair, protein-protein interactions and trans-activation (TA). We investigated the TA activity of 12 BRCA1 variants of unknown clinical significance (VUSs) located in the BRCT domains to aid in the classification of these variants. RESULTS:Twelve BRCA1 VUSs were investigated using a modified version of the dual luciferase TA activity assay (TA assay) that yielded increased sensitivity and sample throughput. Variants were classified according to American College of Medical Genetics and Genomics (ACMG) criteria using TA assay results and available data. In combining our TA-assay results and available data, in accordance with the ACMG guidelines for variant classification, we proposed the following variant classifications: c.5100A>G, c.5326C>T, c.5348T>C and c.5477A>T as likely benign (class 2) variants. c.5075A>C, c.5116G>A and c.5513T>G were likely pathogenic (class 4), whereas c.5096G>A likely represents a likely pathogenic variant with moderate penetrance. Variants c.5123C>T, c.5125G>A, c.5131A>C and c.5504G>A remained classified as VUSs (class 3). CONCLUSIONS:The modified TA assay provides efficient risk assessment of rare missense variants found in the BRCA1 BRCT-domains. We also report that increased post-transfection incubation time yielded a significant increase in TA assay sensitivity.
| S-EPMC6247502 | biostudies-literature
Project description:The functional consequences of missense variants in disease genes are difficult to predict. We assessed if gene expression profiles could distinguish between BRCA1 or BRCA2 pathogenic truncating and missense mutation carriers and familial breast cancer cases whose disease was not attributable to BRCA1 or BRCA2 mutations (BRCAX cases). 72 cell lines from affected women in high-risk breast ovarian families were assayed after exposure to ionising irradiation, including 23 BRCA1 carriers, 22 BRCA2 carriers, and 27 BRCAX individuals. A subset of 10 BRCAX individuals carried rare BRCA1/2 sequence variants considered to be of low clinical significance (LCS). BRCA1 and BRCA2 mutation carriers had similar expression profiles, with some subclustering of missense mutation carriers. The majority of BRCAX individuals formed a distinct cluster, but BRCAX individuals with LCS variants had expression profiles similar to BRCA1/2 mutation carriers. Gaussian Process Classifier predicted BRCA1, BRCA2 and BRCAX status, with a maximum of 62% accuracy, and prediction accuracy decreased with inclusion of BRCAX samples carrying an LCS variant, and inclusion of pathogenic missense carriers. Similarly, prediction of mutation status with gene lists derived using Support Vector Machines was good for BRCAX samples without an LCS variant (82-94%), poor for BRCAX with an LCS (40-50%), and improved for pathogenic BRCA1/2 mutation carriers when the gene list used for prediction was appropriate to mutation effect being tested (71-100%). This study indicates that mutation effect, and presence of rare variants possibly associated with a low risk of cancer, must be considered in the development of array-based assays of variant pathogenicity.
| S-EPMC2375115 | biostudies-literature
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.
| S-EPMC3660339 | biostudies-literature
Project description:BackgroundBRCA1 is a tumour suppressor with pleiotropic actions. Germline mutations in BRCA1 are responsible for a large proportion of breast-ovarian cancer families. Several missense variants have been identified throughout the gene but because of lack of information about their impact on the function of BRCA1, predictive testing is not always informative. Classification of missense variants into deleterious/high risk or neutral/low clinical significance is essential to identify individuals at risk.ObjectiveTo investigate a panel of missense variants.Methods and resultsThe panel was investigated in a comprehensive framework that included (1) a functional assay based on transcription activation; (2) segregation analysis and a method of using incomplete pedigree data to calculate the odds of causality; (3) a method based on interspecific sequence variation. It was shown that the transcriptional activation assay could be used as a test to characterise mutations in the carboxy-terminus region of BRCA1 encompassing residues 1396-1863. Thirteen missense variants (H1402Y, L1407P, H1421Y, S1512I, M1628T, M1628V, T1685I, G1706A, T1720A, A1752P, G1788V, V1809F, and W1837R) were specifically investigated.ConclusionsWhile individual classification schemes for BRCA1 alleles still present limitations, a combination of several methods provides a more powerful way of identifying variants that are causally linked to a high risk of breast and ovarian cancer. The framework presented here brings these variants nearer to clinical applicability.
| S-EPMC1735988 | biostudies-literature
Project description:IntroductionUnclassified variants (UVs) in the BRCA1/BRCA2 genes are a frequent problem in counseling breast cancer and/or ovarian cancer families. Information about cancer family history is usually available, but has rarely been used to evaluate UVs. The aim of the present study was to identify which is the best combination of clinical parameters that can predict whether a UV is deleterious, to be used for the classification of UVs.MethodsWe developed logistic regression models with the best combination of clinical features that distinguished a positive control of BRCA pathogenic variants (115 families) from a negative control population of BRCA variants initially classified as UVs and later considered neutral (38 families).ResultsThe models included a combination of BRCAPRO scores, Myriad scores, number of ovarian cancers in the family, the age at diagnosis, and the number of persons with ovarian tumors and/or breast tumors. The areas under the receiver operating characteristic curves were respectively 0.935 and 0.836 for the BRCA1 and BRCA2 models. For each model, the minimum receiver operating characteristic distance (respectively 90% and 78% specificity for BRCA1 and BRCA2) was chosen as the cutoff value to predict which UVs are deleterious from a study population of 12 UVs, present in 59 Dutch families. The p.S1655F, p.R1699W, and p.R1699Q variants in BRCA1 and the p.Y2660D, p.R2784Q, and p.R3052W variants in BRCA2 are classified as deleterious according to our models. The predictions of the p.L246V variant in BRCA1 and of the p.Y42C, p.E462G, p.R2888C, and p.R3052Q variants in BRCA2 are in agreement with published information of them being neutral. The p.R2784W variant in BRCA2 remains uncertain.ConclusionsThe present study shows that these developed models are useful to classify UVs in clinical genetic practice.
| S-EPMC2687711 | biostudies-literature