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Assessment of the InSiGHT Interpretation Criteria for the Clinical Classification of 24 MLH1 and MSH2 Gene Variants.

Identifieur interne : 001153 ( Main/Exploration ); précédent : 001152; suivant : 001154

Assessment of the InSiGHT Interpretation Criteria for the Clinical Classification of 24 MLH1 and MSH2 Gene Variants.

Auteurs : Rossella Tricarico [Italie] ; Mariann Kasela [Finlande] ; Cristina Mareni [Italie] ; Bryony A. Thompson [États-Unis] ; Aurélie Drouet [France] ; Lucia Staderini [Italie] ; Greta Gorelli [Italie] ; Francesca Crucianelli [Italie] ; Valentina Ingrosso [Italie] ; Jukka Kantelinen [Finlande] ; Laura Papi [Italie] ; Maria De Angioletti [Italie] ; Margherita Berardi [Italie] ; Pascaline Gaildrat [France] ; Omar Soukarieh [France] ; Daniela Turchetti [Italie] ; Alexandra Martins [France] ; Amanda B. Spurdle [Australie] ; Minna Nyström [Finlande] ; Maurizio Genuardi [Italie]

Source :

RBID : pubmed:27629256

Abstract

Pathogenicity assessment of DNA variants in disease genes to explain their clinical consequences is an integral component of diagnostic molecular testing. The International Society for Gastrointestinal Hereditary Tumors (InSiGHT) has developed specific criteria for the interpretation of mismatch repair (MMR) gene variants. Here, we performed a systematic investigation of 24 MLH1 and MSH2 variants. The assessments were done by analyzing population frequency, segregation, tumor molecular characteristics, RNA effects, protein expression levels, and in vitro MMR activity. Classifications were confirmed for 15 variants and changed for three, and for the first time determined for six novel variants. Overall, based on our results, we propose the introduction of some refinements to the InSiGHT classification rules. The proposed changes have the advantage of homogenizing the InSIGHT interpretation criteria with those set out by the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium for the BRCA1/BRCA2 genes. We also observed that the addition of only few clinical data was sufficient to obtain a more stable classification for variants considered as "likely pathogenic" or "likely nonpathogenic." This shows the importance of obtaining as many as possible points of evidence for variant interpretation, especially from the clinical setting.

DOI: 10.1002/humu.23117
PubMed: 27629256


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<name sortKey="Gorelli, Greta" sort="Gorelli, Greta" uniqKey="Gorelli G" first="Greta" last="Gorelli">Greta Gorelli</name>
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<name sortKey="Crucianelli, Francesca" sort="Crucianelli, Francesca" uniqKey="Crucianelli F" first="Francesca" last="Crucianelli">Francesca Crucianelli</name>
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<name sortKey="Ingrosso, Valentina" sort="Ingrosso, Valentina" uniqKey="Ingrosso V" first="Valentina" last="Ingrosso">Valentina Ingrosso</name>
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<nlm:affiliation>Department of Biosciences, Division of Genetics, University of Helsinki, Helsinki, Finland.</nlm:affiliation>
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<name sortKey="Papi, Laura" sort="Papi, Laura" uniqKey="Papi L" first="Laura" last="Papi">Laura Papi</name>
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<nlm:affiliation>Department of Biomedical, Experimental and Clinical Sciences, Medical Genetics Unit, University of Florence, Florence, Italy.</nlm:affiliation>
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<name sortKey="De Angioletti, Maria" sort="De Angioletti, Maria" uniqKey="De Angioletti M" first="Maria" last="De Angioletti">Maria De Angioletti</name>
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<wicri:regionArea>Inserm-U1079-IRIB, Normandy Centre for Genomic and Personalized Medicine, University of Rouen, Rouen</wicri:regionArea>
<placeName>
<region type="region">Région Normandie</region>
<region type="old region">Haute-Normandie</region>
<settlement type="city">Rouen</settlement>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Soukarieh, Omar" sort="Soukarieh, Omar" uniqKey="Soukarieh O" first="Omar" last="Soukarieh">Omar Soukarieh</name>
<affiliation wicri:level="3">
<nlm:affiliation>Inserm-U1079-IRIB, Normandy Centre for Genomic and Personalized Medicine, University of Rouen, Rouen, France.</nlm:affiliation>
<country xml:lang="fr">France</country>
<wicri:regionArea>Inserm-U1079-IRIB, Normandy Centre for Genomic and Personalized Medicine, University of Rouen, Rouen</wicri:regionArea>
<placeName>
<region type="region">Région Normandie</region>
<region type="old region">Haute-Normandie</region>
<settlement type="city">Rouen</settlement>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Turchetti, Daniela" sort="Turchetti, Daniela" uniqKey="Turchetti D" first="Daniela" last="Turchetti">Daniela Turchetti</name>
<affiliation wicri:level="1">
<nlm:affiliation>Medical Genetics, Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy.</nlm:affiliation>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>Medical Genetics, Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna</wicri:regionArea>
<wicri:noRegion>Bologna</wicri:noRegion>
</affiliation>
</author>
<author>
<name sortKey="Martins, Alexandra" sort="Martins, Alexandra" uniqKey="Martins A" first="Alexandra" last="Martins">Alexandra Martins</name>
<affiliation wicri:level="3">
<nlm:affiliation>Inserm-U1079-IRIB, Normandy Centre for Genomic and Personalized Medicine, University of Rouen, Rouen, France.</nlm:affiliation>
<country xml:lang="fr">France</country>
<wicri:regionArea>Inserm-U1079-IRIB, Normandy Centre for Genomic and Personalized Medicine, University of Rouen, Rouen</wicri:regionArea>
<placeName>
<region type="region">Région Normandie</region>
<region type="old region">Haute-Normandie</region>
<settlement type="city">Rouen</settlement>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Spurdle, Amanda B" sort="Spurdle, Amanda B" uniqKey="Spurdle A" first="Amanda B" last="Spurdle">Amanda B. Spurdle</name>
<affiliation wicri:level="1">
<nlm:affiliation>Genetics and Computational Biology Department, QIMR Berghofer Medical Research Institute, Brisbane, Australia.</nlm:affiliation>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Genetics and Computational Biology Department, QIMR Berghofer Medical Research Institute, Brisbane</wicri:regionArea>
<wicri:noRegion>Brisbane</wicri:noRegion>
</affiliation>
</author>
<author>
<name sortKey="Nystrom, Minna" sort="Nystrom, Minna" uniqKey="Nystrom M" first="Minna" last="Nyström">Minna Nyström</name>
<affiliation wicri:level="4">
<nlm:affiliation>Department of Biosciences, Division of Genetics, University of Helsinki, Helsinki, Finland.</nlm:affiliation>
<country xml:lang="fr">Finlande</country>
<wicri:regionArea>Department of Biosciences, Division of Genetics, University of Helsinki, Helsinki</wicri:regionArea>
<orgName type="university">Université d'Helsinki</orgName>
<placeName>
<settlement type="city">Helsinki</settlement>
<region type="région" nuts="2">Uusimaa</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Genuardi, Maurizio" sort="Genuardi, Maurizio" uniqKey="Genuardi M" first="Maurizio" last="Genuardi">Maurizio Genuardi</name>
<affiliation wicri:level="1">
<nlm:affiliation>Department of Biomedical, Experimental and Clinical Sciences, Medical Genetics Unit, University of Florence, Florence, Italy.</nlm:affiliation>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>Department of Biomedical, Experimental and Clinical Sciences, Medical Genetics Unit, University of Florence, Florence</wicri:regionArea>
<wicri:noRegion>Florence</wicri:noRegion>
</affiliation>
</author>
</analytic>
<series>
<title level="j">Human mutation</title>
<idno type="eISSN">1098-1004</idno>
<imprint>
<date when="2017" type="published">2017</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc>
<textClass></textClass>
</profileDesc>
</teiHeader>
<front>
<div type="abstract" xml:lang="en">Pathogenicity assessment of DNA variants in disease genes to explain their clinical consequences is an integral component of diagnostic molecular testing. The International Society for Gastrointestinal Hereditary Tumors (InSiGHT) has developed specific criteria for the interpretation of mismatch repair (MMR) gene variants. Here, we performed a systematic investigation of 24 MLH1 and MSH2 variants. The assessments were done by analyzing population frequency, segregation, tumor molecular characteristics, RNA effects, protein expression levels, and in vitro MMR activity. Classifications were confirmed for 15 variants and changed for three, and for the first time determined for six novel variants. Overall, based on our results, we propose the introduction of some refinements to the InSiGHT classification rules. The proposed changes have the advantage of homogenizing the InSIGHT interpretation criteria with those set out by the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium for the BRCA1/BRCA2 genes. We also observed that the addition of only few clinical data was sufficient to obtain a more stable classification for variants considered as "likely pathogenic" or "likely nonpathogenic." This shows the importance of obtaining as many as possible points of evidence for variant interpretation, especially from the clinical setting.</div>
</front>
</TEI>
<affiliations>
<list>
<country>
<li>Australie</li>
<li>Finlande</li>
<li>France</li>
<li>Italie</li>
<li>États-Unis</li>
</country>
<region>
<li>Haute-Normandie</li>
<li>Région Normandie</li>
<li>Utah</li>
<li>Uusimaa</li>
</region>
<settlement>
<li>Helsinki</li>
<li>Rouen</li>
</settlement>
<orgName>
<li>Université d'Helsinki</li>
</orgName>
</list>
<tree>
<country name="Italie">
<noRegion>
<name sortKey="Tricarico, Rossella" sort="Tricarico, Rossella" uniqKey="Tricarico R" first="Rossella" last="Tricarico">Rossella Tricarico</name>
</noRegion>
<name sortKey="Berardi, Margherita" sort="Berardi, Margherita" uniqKey="Berardi M" first="Margherita" last="Berardi">Margherita Berardi</name>
<name sortKey="Crucianelli, Francesca" sort="Crucianelli, Francesca" uniqKey="Crucianelli F" first="Francesca" last="Crucianelli">Francesca Crucianelli</name>
<name sortKey="De Angioletti, Maria" sort="De Angioletti, Maria" uniqKey="De Angioletti M" first="Maria" last="De Angioletti">Maria De Angioletti</name>
<name sortKey="Genuardi, Maurizio" sort="Genuardi, Maurizio" uniqKey="Genuardi M" first="Maurizio" last="Genuardi">Maurizio Genuardi</name>
<name sortKey="Gorelli, Greta" sort="Gorelli, Greta" uniqKey="Gorelli G" first="Greta" last="Gorelli">Greta Gorelli</name>
<name sortKey="Ingrosso, Valentina" sort="Ingrosso, Valentina" uniqKey="Ingrosso V" first="Valentina" last="Ingrosso">Valentina Ingrosso</name>
<name sortKey="Mareni, Cristina" sort="Mareni, Cristina" uniqKey="Mareni C" first="Cristina" last="Mareni">Cristina Mareni</name>
<name sortKey="Papi, Laura" sort="Papi, Laura" uniqKey="Papi L" first="Laura" last="Papi">Laura Papi</name>
<name sortKey="Staderini, Lucia" sort="Staderini, Lucia" uniqKey="Staderini L" first="Lucia" last="Staderini">Lucia Staderini</name>
<name sortKey="Turchetti, Daniela" sort="Turchetti, Daniela" uniqKey="Turchetti D" first="Daniela" last="Turchetti">Daniela Turchetti</name>
</country>
<country name="Finlande">
<region name="Uusimaa">
<name sortKey="Kasela, Mariann" sort="Kasela, Mariann" uniqKey="Kasela M" first="Mariann" last="Kasela">Mariann Kasela</name>
</region>
<name sortKey="Kantelinen, Jukka" sort="Kantelinen, Jukka" uniqKey="Kantelinen J" first="Jukka" last="Kantelinen">Jukka Kantelinen</name>
<name sortKey="Nystrom, Minna" sort="Nystrom, Minna" uniqKey="Nystrom M" first="Minna" last="Nyström">Minna Nyström</name>
</country>
<country name="États-Unis">
<region name="Utah">
<name sortKey="Thompson, Bryony A" sort="Thompson, Bryony A" uniqKey="Thompson B" first="Bryony A" last="Thompson">Bryony A. Thompson</name>
</region>
</country>
<country name="France">
<region name="Région Normandie">
<name sortKey="Drouet, Aurelie" sort="Drouet, Aurelie" uniqKey="Drouet A" first="Aurélie" last="Drouet">Aurélie Drouet</name>
</region>
<name sortKey="Gaildrat, Pascaline" sort="Gaildrat, Pascaline" uniqKey="Gaildrat P" first="Pascaline" last="Gaildrat">Pascaline Gaildrat</name>
<name sortKey="Martins, Alexandra" sort="Martins, Alexandra" uniqKey="Martins A" first="Alexandra" last="Martins">Alexandra Martins</name>
<name sortKey="Soukarieh, Omar" sort="Soukarieh, Omar" uniqKey="Soukarieh O" first="Omar" last="Soukarieh">Omar Soukarieh</name>
</country>
<country name="Australie">
<noRegion>
<name sortKey="Spurdle, Amanda B" sort="Spurdle, Amanda B" uniqKey="Spurdle A" first="Amanda B" last="Spurdle">Amanda B. Spurdle</name>
</noRegion>
</country>
</tree>
</affiliations>
</record>

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