scholarly journals Functional Assays for Analysis of Variants of Uncertain Significance inBRCA2

2013 ◽  
Vol 35 (2) ◽  
pp. 151-164 ◽  
Author(s):  
Lucia Guidugli ◽  
Aura Carreira ◽  
Sandrine M. Caputo ◽  
Asa Ehlen ◽  
Alvaro Galli ◽  
...  
Keyword(s):  
Variants Of Uncertain Significance ◽  
Functional Assays ◽  
Uncertain Significance

scholarly journals Functional assays provide a robust tool for the clinical annotation of genetic variants of uncertain significance

2016 ◽  
Vol 1 (1) ◽  
Author(s):  
Nicholas T Woods ◽  
Rebekah Baskin ◽  
Volha Golubeva ◽  
Ankita Jhuraney ◽  
Giuliana De-Gregoriis ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Variants Of Uncertain Significance ◽  
Functional Assays ◽  
Uncertain Significance ◽  
Clinical Annotation

scholarly journals Functional Assays for Classification of BRCA2 Variants of Uncertain Significance

2008 ◽  
Vol 68 (9) ◽  
pp. 3523-3531 ◽  
Author(s):  
Daniel J. Farrugia ◽  
Mukesh K. Agarwal ◽  
Vernon S. Pankratz ◽  
Amie M. Deffenbaugh ◽  
Dmitry Pruss ◽  
...  
Keyword(s):  
Variants Of Uncertain Significance ◽  
Functional Assays ◽  
Uncertain Significance

scholarly journals Classification of MSH6 Variants of Uncertain Significance Using Functional Assays

2021 ◽  
Vol 22 (16) ◽  
pp. 8627
Author(s):  
Jane H. Frederiksen ◽  
Sara B. Jensen ◽  
Zeynep Tümer ◽  
Thomas v. O. Hansen
Keyword(s):  
Large Fraction ◽  
Mrna Level ◽  
Genetic Diagnosis ◽  
Cancer Surveillance ◽  
Future Perspective ◽  
Clinical Effects ◽  
Variants Of Uncertain Significance ◽  
Functional Assays ◽  
Mmr Genes ◽  
Uncertain Significance

Lynch syndrome (LS) is one of the most common hereditary cancer predisposition syndromes worldwide. Individuals with LS have a high risk of developing colorectal or endometrial cancer, as well as several other cancers. LS is caused by autosomal dominant pathogenic variants in one of the DNA mismatch repair (MMR) genes MLH1, MSH2, PMS2 or MSH6, and typically include truncating variants, such as frameshift, nonsense or splicing variants. However, a significant number of missense, intronic, or silent variants, or small in-frame insertions/deletions, are detected during genetic screening of the MMR genes. The clinical effects of these variants are often more difficult to predict, and a large fraction of these variants are classified as variants of uncertain significance (VUS). It is pivotal for the clinical management of LS patients to have a clear genetic diagnosis, since patients benefit widely from screening, preventive and personal therapeutic measures. Moreover, in families where a pathogenic variant is identified, testing can be offered to family members, where non-carriers can be spared frequent surveillance, while carriers can be included in cancer surveillance programs. It is therefore important to reclassify VUSs, and, in this regard, functional assays can provide insight into the effect of a variant on the protein or mRNA level. Here, we briefly describe the disorders that are related to MMR deficiency, as well as the structure and function of MSH6. Moreover, we review the functional assays that are used to examine VUS identified in MSH6 and discuss the results obtained in relation to the ACMG/AMP PS3/BS3 criterion. We also provide a compiled list of the MSH6 variants examined by these assays. Finally, we provide a future perspective on high-throughput functional analyses with specific emphasis on the MMR genes.

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.

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