Consequences of germline variation disrupting the constitutional translational initiation codon start sites of MLH1 and BRCA2: Use of potential alternative start sites and implications for predicting variant pathogenicity

Parsons, Michael T., Whiley, Phillip J., Beesley, Jonathan, Drost, Mark, de Wind, Neils, Thompson, Bryony A., Marquart, Lousie, Hopper, John L., Jenkins, Mark A., Brown, Melissa A., Tucker, Kathy, Warwick, Linda, Buchanan, Daniel D., Spurdle, Amanda B. and Australasian Colorectal Cancer Family Registry (2013) Consequences of germline variation disrupting the constitutional translational initiation codon start sites of MLH1 and BRCA2: Use of potential alternative start sites and implications for predicting variant pathogenicity. Molecular Carcinogenesis, 54 7: 513-522. doi:10.1002/mc.22116

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Author Parsons, Michael T.
Whiley, Phillip J.
Beesley, Jonathan
Drost, Mark
de Wind, Neils
Thompson, Bryony A.
Marquart, Lousie
Hopper, John L.
Jenkins, Mark A.
Brown, Melissa A.
Tucker, Kathy
Warwick, Linda
Buchanan, Daniel D.
Spurdle, Amanda B.
Australasian Colorectal Cancer Family Registry
Title Consequences of germline variation disrupting the constitutional translational initiation codon start sites of MLH1 and BRCA2: Use of potential alternative start sites and implications for predicting variant pathogenicity
Journal name Molecular Carcinogenesis   Check publisher's open access policy
ISSN 0899-1987
1098-2744
Publication date 2013-01-01
Sub-type Article (original research)
DOI 10.1002/mc.22116
Volume 54
Issue 7
Start page 513
End page 522
Total pages 10
Place of publication Hoboken NJ United States
Publisher John Wiley & Sons
Collection year 2014
Language eng
Formatted abstract
Variants that disrupt the translation initiation sequences in cancer predisposition genes are generally assumed to be deleterious. However, few studies have validated these assumptions with functional and clinical data. Two cancer syndrome gene variants likely to affect native translation initiation were identified by clinical genetic testing: MLH1:c.1A>G p.(Met1?) and BRCA2:c.67+3A>G. In vitro GFP-reporter assays were conducted to assess the consequences of translation initiation disruption on alternative downstream initiation codon usage. Analysis of MLH1:c.1A>G p.(Met1?) showed that translation was mostly initiated at an in-frame position 103 nucleotides downstream, but also at two ATG sequences downstream. The protein product encoded by the in-frame transcript initiating from position c.103 showed loss of in vitro mismatch repair activity comparable to known pathogenic mutations. BRCA2:c.67+3A>G was shown by mRNA analysis to result in an aberrantly spliced transcript deleting exon 2 and the consensus ATG site. In the absence of exon 2, translation initiated mostly at an out-of-frame ATG 323 nucleotides downstream, and to a lesser extent at an in-frame ATG 370 nucleotides downstream. Initiation from any of the downstream alternative sites tested in both genes would lead to loss of protein function, but further clinical data is required to confirm if these variants are associated with a high cancer risk. Importantly, our results highlight the need for caution in interpreting the functional and clinical consequences of variation that leads to disruption of the initiation codon, since translation may not necessarily occur from the first downstream alternative start site, or from a single alternative start site.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Article first published online: 2 DEC 2013

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
School of Medicine Publications
 
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Created: Mon, 28 Apr 2014, 15:24:28 EST by Matthew Lamb on behalf of School of Medicine