Clinical relevance of rare germline sequence variants in cancer genes: evolution and application of classification models

Spurdle, Amanda B.

doi:10.1016/j.gde.2010.03.009

Cited by 36 publications

(32 citation statements)

References 51 publications

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“…[3][4][5][6][7][8][9][10][11][12] An increasing number of groups are trying to classify UVs using these recommendations, but most of them focus on the BRCA1 and BRCA2 genes, for which a multifactorial likelihood classification has already been developed and refined. Instead, for MMR genes, there are not well-established models or well-characterized features 42 so that, at the time of writing, a very few groups have attempted to classify MMR UVs with the Bayesian likelihood method. The study by Arnold et al 24 investigated several variants, three of which are in common with our data (MLH1 c.307-29CϾA, c.1039-8 TϾA and MSH2 p.Gly322Asp): only c.307-29CϾA was analyzed by a similar comprehensive approach and assigned to class 3, as it is in our study.…”

Section: Discussionmentioning

confidence: 99%

Integrated analysis of unclassified variants in mismatch repair genes

Pastrello

Marroni

et al. 2011

Genetics in Medicine

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Purpose: Lynch syndrome is a genetic disease that predisposes to colorectal tumors, caused by mutation in mismatch repair genes. The use of genetic tests to identify mutation carriers does not always give perfectly clear results, as happens when an unclassified variant is found. This study aimed to define the pathogenic role of 35 variants present in MSH2, MLH1, MSH6, and PMS2 genes identified in our 15-year case study. Methods: We collected clinical and molecular data of all carriers, and then we analyzed the variants pathogenic role with web tools and molecular analyses. Using a Bayesian approach, we derived a posterior probability of pathogenicity and classified each variant according to a standardized five-class system. Results: The MSH2 p.Pro349Arg, p.Met688Arg, the MLH1 p.Gly67Arg, p.Thr82Ala, p.Lys618Ala, the MSH6 p.Ala1236Pro, and the PMS2 p.Arg20Gln were classified as pathogenic, and the MSH2 p.Cys697Arg and the PMS2 p.Ser46Ile were classified as likely pathogenic. Seven variants were likely nonpathogenic, 3 were nonpathogenic, and 16 remained uncertain. Conclusion: Quantitative assessment of several parameters and their integration in a multifactorial likelihood model is the method of choice for classifying the variants. As such classifications can be associated with surveillance and testing recommendations, the results and the method developed in our study can be useful for helping laboratory geneticists in evaluation of genetic tests and clinicians in the management of carriers. Genet Med 2011:13(2):115-124.

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Section: Discussionmentioning

confidence: 99%

Integrated analysis of unclassified variants in mismatch repair genes

Pastrello

Marroni

et al. 2011

Genetics in Medicine

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“…This is finding application to diseases including breast cancer and Lynch syndrome (Spurdle, 2010). However, application of this method is not routinely accepted in diagnostic practice, and is suited to projects or communities with centralised resources and a committee approach to variant classification.…”

Section: An Integrated Evaluation Of Sequence Variantsmentioning

confidence: 99%

Arvelige perifere nevropatier diagnostisert ved dypsekvensering

Høyer¹,

Busk²,

Holla³

et al. 2015

Tidsskriftet

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“…The proposed algorithm is based on the previously established integrated evaluation or multifactorial likelihood model used for BRCA1/2 unclassified variants [Goldgar et al, 2004]. This approach can incorporate several independent variables relevant to pathogenicity assessment, such as segregation data, personal and family history of cancer, pathology data (e.g., histology, MSI, IHC, BRAF), in silico assessment of substitution effects and evolutionary conservation, and predicted or demonstrated RNA effects [Spurdle, 2010].…”

Section: Models To Evaluate the Clinical Significance Of Mmr Gene Varmentioning

confidence: 99%