Co-occurrence of nonsense mutations in MSH6 and MSH2 in Lynch syndrome families evidencing that not all truncating mutations are equal View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2016-02

AUTHORS

Carla Pinto, Manuela Pinheiro, Ana Peixoto, Catarina Santos, Isabel Veiga, Patrícia Rocha, Pedro Pinto, Paula Lopes, Manuela Baptista, Rui Henrique, Manuel R Teixeira

ABSTRACT

The majority of pathogenic mismatch repair (MMR) gene mutations detected in Lynch syndrome patients are truncating (frameshift or nonsense). However, the classification of terminal truncating mutations is sometimes difficult and predictive testing based on non-deleterious variants can have very serious consequences. Here, we report eight probands that have two germline nonsense mutations, namely MSH6 c.1030C>T, p.(Gln344Ter) and MSH2 c.2785C>T, p.(Arg929Ter), and one additional patient who presented only the MSH2 mutation previously reported as deleterious. The novel MSH6 truncating mutation was classified as deleterious, as it is predicted to encode a protein with loss of 1017 amino acid residues. The MSH2 mutation, which is expected to encode a protein lacking six amino acid residues, was considered a variant of unknown significance. Five tumors of the eight double-mutant individuals had normal MSH2 expression, whereas MSH6 immunoexpression was lost in all evaluable cases. None of the variants were detected in normal controls or associated with other MMR germline mutations in our series. This study emphasizes that not all truncating mutations are equal and that one must be cautious in the interpretation of the presumed deleterious effect of terminal frameshift or nonsense mutations. More... »

PAGES

151-156

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/jhg.2015.124

DOI

http://dx.doi.org/10.1038/jhg.2015.124

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1005664224

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/26446363


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39 schema:description The majority of pathogenic mismatch repair (MMR) gene mutations detected in Lynch syndrome patients are truncating (frameshift or nonsense). However, the classification of terminal truncating mutations is sometimes difficult and predictive testing based on non-deleterious variants can have very serious consequences. Here, we report eight probands that have two germline nonsense mutations, namely MSH6 c.1030C>T, p.(Gln344Ter) and MSH2 c.2785C>T, p.(Arg929Ter), and one additional patient who presented only the MSH2 mutation previously reported as deleterious. The novel MSH6 truncating mutation was classified as deleterious, as it is predicted to encode a protein with loss of 1017 amino acid residues. The MSH2 mutation, which is expected to encode a protein lacking six amino acid residues, was considered a variant of unknown significance. Five tumors of the eight double-mutant individuals had normal MSH2 expression, whereas MSH6 immunoexpression was lost in all evaluable cases. None of the variants were detected in normal controls or associated with other MMR germline mutations in our series. This study emphasizes that not all truncating mutations are equal and that one must be cautious in the interpretation of the presumed deleterious effect of terminal frameshift or nonsense mutations.
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