scholarly journals Author Correction: Methods for Scarless, Selection-Free Generation of Human Cells and Allele-Specific Functional Analysis of Disease-Associated SNPs and Variants of Uncertain Significance

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Nicole B. Coggins ◽  
Jacob Stultz ◽  
Henriette O’Geen ◽  
Luis G. Carvajal-Carmona ◽  
David J. Segal
Keyword(s):  
Functional Analysis ◽  
Human Cells ◽  
Variants Of Uncertain Significance ◽  
Uncertain Significance ◽  
Allele Specific ◽  
Free Generation

A putative Lynch syndrome family carrying MSH2 and MSH6 variants of uncertain significance—functional analysis reveals the pathogenic one

2011 ◽  
Vol 10 (3) ◽  
pp. 515-520 ◽  
Author(s):  
Jukka Kantelinen ◽  
Thomas v. O. Hansen ◽  
Minttu Kansikas ◽  
Lotte Nylandsted Krogh ◽  
Mari K. Korhonen ◽  
...  
Keyword(s):  
Functional Analysis ◽  
Lynch Syndrome ◽  
Variants Of Uncertain Significance ◽  
Uncertain Significance ◽  
Lynch Syndrome Family

scholarly journals Functional analysis of BRCA1 missense variants of uncertain significance in Japanese breast cancer families

2013 ◽  
Vol 58 (9) ◽  
pp. 618-621 ◽  
Author(s):  
Shogo Kawaku ◽  
Rieko Sato ◽  
Hao Song ◽  
Yuko Bando ◽  
Tadao Arinami ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Functional Analysis ◽  
Variants Of Uncertain Significance ◽  
Missense Variants ◽  
Uncertain Significance

Functional analysis of patient-derived PALB2 missense variants of uncertain significance.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 1531-1531
Author(s):  
Shijie Wu ◽  
Jiaojiao Zhou ◽  
Yiding Chen
Keyword(s):  
Breast Cancer ◽  
Functional Analysis ◽  
In Silico ◽  
Cancer Genetic Counseling ◽  
Wild Type ◽  
Variants Of Uncertain Significance ◽  
Missense Variants ◽  
Pathogenic Variants ◽  
Uncertain Significance ◽  
The Impact

1531 Background: Inherited PALB2 pathogenic variants are associated with an increased lifetime risk for breast cancer development. However, the interpretation of numerous PALB2 missense variants of uncertain significance (VUS) identified in germline genetic testing remains a challenge. Here, we assessed the impact of breast cancer patient-derived VUS on PALB2 function and identified pathogenic PALB2 missense variants that may increase cancer risk. Methods: A total of seven potentially pathogenic PALB2 VUS identified in 2,279 breast cancer patients were selected for functional analysis. All these selected VUS were assessed by SIFT, Align-GVGD, and PolyPhen2 in silico and were predicted to be deleterious by at least two in silico algorithms. The p.L35P [c.104T > C] variant was also included, for which pathogenicity has been recently confirmed. The effects of the VUS on the homologous recombination (HR) activity of PALB2 were tested by U2OS/DR-GFP reporting system. Functional characterization was further validated by protein co-immunoprecipitation and RAD51 recruitment assay. Results: PALB2 variants p.L24F [c.72G > C] and p.L35P [c.104T > C] showed the most significant disruption to the HR activity of PALB2 relative to the wild-type condition, retaining only 52.2% ( p = 0.0013) and 8.5% ( p < 0.0001) of HR activity respectively. Moderate but statistically significant HR deficiency was observed for four other variants (p.P405A [c.1213C > G], p.T1012I [c.3035C > T], p.E1018D [c.3054G > C], and p.T1099M [c.3296C > T]). We found no statistical differences for the p.K628N [c.1884G > T] and p.R663C [c.1987C > T] in the HR activity compared to wild-type PALB2. The p.L24F and p.L35P variants compromised the BRCA1-PALB2 interaction and reduced RAD51 foci formation in response to DNA damage. Conclusions: We have identified a novel patient-derived pathogenic PALB2 missense variant, p.L24F [c.72G > C], that compromises PALB2-mediated HR activity. We suggest the integration of the identified pathogenic variants into breast cancer genetic counseling and individualized treatment regimens for better clinical outcomes.

scholarly journals Actions and Uncertainty: How Prenatally Diagnosed Variants of Uncertain Significance Become Actionable

2019 ◽  
Vol 49 ◽  
pp. S61-S71 ◽  
Author(s):  
Allison Werner-Lin ◽  
Judith L. M. Mccoyd ◽  
Barbara A. Bernhardt
Keyword(s):  
Variants Of Uncertain Significance ◽  
Uncertain Significance

scholarly journals Lynch Syndrome Limbo: Patient Understanding of Variants of Uncertain Significance

2017 ◽  
Vol 26 (4) ◽  
pp. 866-877 ◽  
Author(s):  
Ilana Solomon ◽  
Elizabeth Harrington ◽  
Gillian Hooker ◽  
Lori Erby ◽  
Jennifer Axilbund ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Patient Understanding ◽  
Variants Of Uncertain Significance ◽  
Uncertain Significance

scholarly journals Functional Annotation of TNNT2 Variants of Uncertain Significance With Genome-Edited Cardiomyocytes

Circulation ◽  
2018 ◽  
Vol 138 (24) ◽  
pp. 2852-2854 ◽  
Author(s):  
Wenjian Lv ◽  
Lyon Qiao ◽  
Nataliya Petrenko ◽  
Wenjun Li ◽  
Anjali T. Owens ◽  
...  
Keyword(s):  
Functional Annotation ◽  
Variants Of Uncertain Significance ◽  
Uncertain Significance

scholarly journals Assessing BRCA1 activity in DNA damage repair using human induced pluripotent stem cells as an approach to assist classification of BRCA1 variants of uncertain significance

PLoS ONE ◽  
2021 ◽  
Vol 16 (12) ◽  
pp. e0260852
Author(s):  
Meryem Ozgencil ◽  
Julian Barwell ◽  
Marc Tischkowitz ◽  
Louise Izatt ◽  
Ian Kesterton ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Repair ◽  
Ips Cells ◽  
Variants Of Uncertain Significance ◽  
Cellular Models ◽  
Pathogenic Variants ◽  
Damage Repair ◽  
Uncertain Significance ◽  
Induced Pluripotent ◽  
The Impact

Establishing a universally applicable protocol to assess the impact of BRCA1 variants of uncertain significance (VUS) expression is a problem which has yet to be resolved despite major progresses have been made. The numerous difficulties which must be overcome include the choices of cellular models and functional assays. We hypothesised that the use of induced pluripotent stem (iPS) cells might facilitate the standardisation of protocols for classification, and could better model the disease process. We generated eight iPS cell lines from patient samples expressing either BRCA1 pathogenic variants, non-pathogenic variants, or BRCA1 VUSs. The impact of these variants on DNA damage repair was examined using a ɣH2AX foci formation assay, a Homologous Repair (HR) reporter assay, and a chromosome abnormality assay. Finally, all lines were tested for their ability to differentiate into mammary lineages in vitro. While the results obtained from the two BRCA1 pathogenic variants were consistent with published data, some other variants exhibited differences. The most striking of these was the BRCA1 variant Y856H (classified as benign), which was unexpectedly found to present a faulty HR repair pathway, a finding linked to the presence of an additional variant in the ATM gene. Finally, all lines were able to differentiate first into mammospheres, and then into more advanced mammary lineages expressing luminal- or basal-specific markers. This study stresses that BRCA1 genetic analysis alone is insufficient to establish a reliable and functional classification for assessment of clinical risk, and that it cannot be performed without considering the other genetic aberrations which may be present in patients. The study also provides promising opportunities for elucidating the physiopathology and clinical evolution of breast cancer, by using iPS cells.

scholarly journals Multi gene panel testing for hereditary breast cancer - is it ready to be used?

2019 ◽  
Author(s):  
Andreea Catana ◽  
Adina Patricia Apostu ◽  
Razvan-Geo Antemie
Keyword(s):  
Breast Cancer ◽  
Hereditary Breast Cancer ◽  
Gene Panel ◽  
Variants Of Uncertain Significance ◽  
Panel Testing ◽  
Brca Genes ◽  
Prophylactic Measures ◽  
Gene Panel Testing ◽  
Uncertain Significance ◽  
High Level

Breast cancer is one of the most common malignancies and the leading cause of death among women worldwide. About 20% of breast cancers are hereditary. Approximately 30% of the mutations have remained negative after testing BRCA1/2 even in families with a Mendelian inheritance pattern for breast cancer. Additional non-BRCA genes have been identified as predisposing for breast cancer. Multi gene panel testing tries to cover and explain the BRCA negative inherited breast cancer, improving efficiency, speed and costs of the breast cancer screening. We identified 23 studies reporting results from individuals who have undergone multi gene panel testing for hereditary breast cancer and noticed a prevalence of 1-12% of non-BRCA genes, but also a high level of variants of uncertain significance. A result with a high level of variants of uncertain significance is likely to be more costly than bring benefits, as well as increase the anxiety for patients. Regarding further development of multi gene panel testing, more research is required to establish both the optimal care of patients with cancer (specific treatments like PARP inhibitors) and the management of unaffected individuals (chemoprevention and/or prophylactic surgeries). Early detection in these patients as well as prophylactic measures will significantly increase the chance of survival. Therefore, multi gene panel testing is not yet ready to be used outside clear guidelines. In conclusion, studies on additional cohorts will be needed to better define the real prevalence, penetrance and the variants of these genes, as well as to describe clear evidence-based guidelines for these patients. 

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