Detailed characterization of MLH1 p.D41H and p.N710D variants coexisting in a Lynch syndrome family with conserved MLH1 expression tumors
Lynch syndrome (LS) is an autosomal dominant cancer‐susceptibility disease caused by inactivating germline mutations in mismatch repair (MMR) genes. Variants of unknown significance (VUS) are often detected in mutational analysis of MMR genes. Here we describe a large family fulfilling Amsterdam I c...
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| Veröffentlicht in: | Clinical genetics 2015-06, Vol.87 (6), p.543-548 |
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| creator | Pineda, M. González-Acosta, M. Thompson, B.A. Sánchez, R. Gómez, C. Martínez-López, J. Perea, J. Caldés, T. Rodríguez, Y. Landolfi, S. Balmaña, J. Lázaro, C. Robles, L. Capellá, G. Rueda, D. |
| description | Lynch syndrome (LS) is an autosomal dominant cancer‐susceptibility disease caused by inactivating germline mutations in mismatch repair (MMR) genes. Variants of unknown significance (VUS) are often detected in mutational analysis of MMR genes. Here we describe a large family fulfilling Amsterdam I criteria carrying two rare VUS in the MLH1 gene: c.121G > C (p.D41H) and c.2128A > G (p.N710D). Collection of clinico‐pathological data, multifactorial analysis, in silico predictions, and functional analyses were used to elucidate the clinical significance of the identified MLH1 VUS. Only the c.121G > C variant cosegregated with LS‐associated tumors in the family. Diagnosed colorectal tumors were microsatellite unstable although immunohistochemical staining revealed no loss of MMR proteins expression. Multifactorial likelihood analysis classified c.2128A > G as a non‐pathogenic variant and c.121G > C as pathogenic. In vitro functional tests revealed impaired MMR activity and diminished expression of c.121G > C. Accordingly, the N710 residue is located in the unconserved MLH1 C‐terminal domain, whereas D41 is highly conserved and located in the ATPase domain. The obtained results will enable adequate genetic counseling of c.121G > C and c.2128A > G variant carriers and their families. Furthermore, they exemplify how cumulative data and comprehensive analyses are mandatory to refine the classification of MMR variants. |
| doi_str_mv | 10.1111/cge.12467 |
| format | Article |
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Variants of unknown significance (VUS) are often detected in mutational analysis of MMR genes. Here we describe a large family fulfilling Amsterdam I criteria carrying two rare VUS in the MLH1 gene: c.121G > C (p.D41H) and c.2128A > G (p.N710D). Collection of clinico‐pathological data, multifactorial analysis, in silico predictions, and functional analyses were used to elucidate the clinical significance of the identified MLH1 VUS. Only the c.121G > C variant cosegregated with LS‐associated tumors in the family. Diagnosed colorectal tumors were microsatellite unstable although immunohistochemical staining revealed no loss of MMR proteins expression. Multifactorial likelihood analysis classified c.2128A > G as a non‐pathogenic variant and c.121G > C as pathogenic. In vitro functional tests revealed impaired MMR activity and diminished expression of c.121G > C. Accordingly, the N710 residue is located in the unconserved MLH1 C‐terminal domain, whereas D41 is highly conserved and located in the ATPase domain. The obtained results will enable adequate genetic counseling of c.121G > C and c.2128A > G variant carriers and their families. Furthermore, they exemplify how cumulative data and comprehensive analyses are mandatory to refine the classification of MMR variants.</description><identifier>ISSN: 0009-9163</identifier><identifier>EISSN: 1399-0004</identifier><identifier>DOI: 10.1111/cge.12467</identifier><identifier>PMID: 25060679</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject>Adaptor Proteins, Signal Transducing - chemistry ; Adaptor Proteins, Signal Transducing - genetics ; Adaptor Proteins, Signal Transducing - metabolism ; Adult ; Age of Onset ; Amino Acid Substitution ; Binding Sites ; Codon ; Colorectal Neoplasms, Hereditary Nonpolyposis - diagnosis ; Colorectal Neoplasms, Hereditary Nonpolyposis - genetics ; Family ; Female ; Gene Expression ; Genetic counseling ; Genetic disorders ; Genetic Variation ; Heterozygote ; HNPCC ; Humans ; Lynch syndrome ; Male ; Middle Aged ; MLH1 ; Models, Molecular ; Mutation ; MutL Protein Homolog 1 ; Nuclear Proteins - chemistry ; Nuclear Proteins - genetics ; Nuclear Proteins - metabolism ; Pedigree ; Protein Conformation ; Protein Interaction Domains and Motifs ; Tumors ; variants of unknown significance</subject><ispartof>Clinical genetics, 2015-06, Vol.87 (6), p.543-548</ispartof><rights>2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd</rights><rights>2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.</rights><rights>2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><orcidid>0000-0001-8655-1839</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fcge.12467$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fcge.12467$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25060679$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Pineda, M.</creatorcontrib><creatorcontrib>González-Acosta, M.</creatorcontrib><creatorcontrib>Thompson, B.A.</creatorcontrib><creatorcontrib>Sánchez, R.</creatorcontrib><creatorcontrib>Gómez, C.</creatorcontrib><creatorcontrib>Martínez-López, J.</creatorcontrib><creatorcontrib>Perea, J.</creatorcontrib><creatorcontrib>Caldés, T.</creatorcontrib><creatorcontrib>Rodríguez, Y.</creatorcontrib><creatorcontrib>Landolfi, S.</creatorcontrib><creatorcontrib>Balmaña, J.</creatorcontrib><creatorcontrib>Lázaro, C.</creatorcontrib><creatorcontrib>Robles, L.</creatorcontrib><creatorcontrib>Capellá, G.</creatorcontrib><creatorcontrib>Rueda, D.</creatorcontrib><title>Detailed characterization of MLH1 p.D41H and p.N710D variants coexisting in a Lynch syndrome family with conserved MLH1 expression tumors</title><title>Clinical genetics</title><addtitle>Clin Genet</addtitle><description>Lynch syndrome (LS) is an autosomal dominant cancer‐susceptibility disease caused by inactivating germline mutations in mismatch repair (MMR) genes. Variants of unknown significance (VUS) are often detected in mutational analysis of MMR genes. Here we describe a large family fulfilling Amsterdam I criteria carrying two rare VUS in the MLH1 gene: c.121G > C (p.D41H) and c.2128A > G (p.N710D). Collection of clinico‐pathological data, multifactorial analysis, in silico predictions, and functional analyses were used to elucidate the clinical significance of the identified MLH1 VUS. Only the c.121G > C variant cosegregated with LS‐associated tumors in the family. Diagnosed colorectal tumors were microsatellite unstable although immunohistochemical staining revealed no loss of MMR proteins expression. Multifactorial likelihood analysis classified c.2128A > G as a non‐pathogenic variant and c.121G > C as pathogenic. In vitro functional tests revealed impaired MMR activity and diminished expression of c.121G > C. Accordingly, the N710 residue is located in the unconserved MLH1 C‐terminal domain, whereas D41 is highly conserved and located in the ATPase domain. The obtained results will enable adequate genetic counseling of c.121G > C and c.2128A > G variant carriers and their families. Furthermore, they exemplify how cumulative data and comprehensive analyses are mandatory to refine the classification of MMR variants.</description><subject>Adaptor Proteins, Signal Transducing - chemistry</subject><subject>Adaptor Proteins, Signal Transducing - genetics</subject><subject>Adaptor Proteins, Signal Transducing - metabolism</subject><subject>Adult</subject><subject>Age of Onset</subject><subject>Amino Acid Substitution</subject><subject>Binding Sites</subject><subject>Codon</subject><subject>Colorectal Neoplasms, Hereditary Nonpolyposis - diagnosis</subject><subject>Colorectal Neoplasms, Hereditary Nonpolyposis - genetics</subject><subject>Family</subject><subject>Female</subject><subject>Gene Expression</subject><subject>Genetic counseling</subject><subject>Genetic disorders</subject><subject>Genetic Variation</subject><subject>Heterozygote</subject><subject>HNPCC</subject><subject>Humans</subject><subject>Lynch syndrome</subject><subject>Male</subject><subject>Middle Aged</subject><subject>MLH1</subject><subject>Models, Molecular</subject><subject>Mutation</subject><subject>MutL Protein Homolog 1</subject><subject>Nuclear Proteins - chemistry</subject><subject>Nuclear Proteins - genetics</subject><subject>Nuclear Proteins - metabolism</subject><subject>Pedigree</subject><subject>Protein Conformation</subject><subject>Protein Interaction Domains and Motifs</subject><subject>Tumors</subject><subject>variants of unknown significance</subject><issn>0009-9163</issn><issn>1399-0004</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkcFy0zAQhjUMHRpSDrwAoxkuXJxKlizZRyZpE6amXCgcNWtZblRsOZXsNuYNeGvUpPSALrs7-_27mn8Rek_JgsZ3rm_NgqZcyFdoRllRJIQQ_hrNYiiSggp2it6GcBdLJrPiDTpNMyKIkMUM_VmZAWxraqy34EEPxtvfMNje4b7BX8sNxbvFitMNBlfH9FpSssIP4C24IWDdm70Ng3W32DoMuJyc3uIwudr3ncENdLad8KMdthF1wfiHuOkw1ex33oTwtGgYu96HM3TSQBvMu-c4RzeXF9-Xm6T8tv6y_FwmllEpE6hyrZmshTS6qkQmCEjOK8I4q1KdZ9CwTHJSSVoL0-RcZiBIDWmdQ00bQdgcfTrO3fn-fjRhUJ0N2rQtONOPQVGREyrztCgi-vE_9K4fvYu_i5TMeUZoXDtHH56psepMrXbeduAn9c_kCJwfgcdo9PTSp0Q9XU_F66nD9dRyfXFIoiI5KqK3Zv-iAP9Lxa7M1M_rtbpkV4KVP6TasL8zspob</recordid><startdate>201506</startdate><enddate>201506</enddate><creator>Pineda, M.</creator><creator>González-Acosta, M.</creator><creator>Thompson, B.A.</creator><creator>Sánchez, R.</creator><creator>Gómez, C.</creator><creator>Martínez-López, J.</creator><creator>Perea, J.</creator><creator>Caldés, T.</creator><creator>Rodríguez, Y.</creator><creator>Landolfi, S.</creator><creator>Balmaña, J.</creator><creator>Lázaro, C.</creator><creator>Robles, L.</creator><creator>Capellá, G.</creator><creator>Rueda, D.</creator><general>Blackwell Publishing Ltd</general><scope>BSCLL</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7TK</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-8655-1839</orcidid></search><sort><creationdate>201506</creationdate><title>Detailed characterization of MLH1 p.D41H and p.N710D variants coexisting in a Lynch syndrome family with conserved MLH1 expression tumors</title><author>Pineda, M. ; González-Acosta, M. ; Thompson, B.A. ; Sánchez, R. ; Gómez, C. ; Martínez-López, J. ; Perea, J. ; Caldés, T. ; Rodríguez, Y. ; Landolfi, S. ; Balmaña, J. ; Lázaro, C. ; Robles, L. ; Capellá, G. ; Rueda, D.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-i3177-ab8cc37d67ecbb6560a744b0343b2c85af35740b71d6ef8475a60da2d8ad1f603</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Adaptor Proteins, Signal Transducing - chemistry</topic><topic>Adaptor Proteins, Signal Transducing - genetics</topic><topic>Adaptor Proteins, Signal Transducing - metabolism</topic><topic>Adult</topic><topic>Age of Onset</topic><topic>Amino Acid Substitution</topic><topic>Binding Sites</topic><topic>Codon</topic><topic>Colorectal Neoplasms, Hereditary Nonpolyposis - diagnosis</topic><topic>Colorectal Neoplasms, Hereditary Nonpolyposis - genetics</topic><topic>Family</topic><topic>Female</topic><topic>Gene Expression</topic><topic>Genetic counseling</topic><topic>Genetic disorders</topic><topic>Genetic Variation</topic><topic>Heterozygote</topic><topic>HNPCC</topic><topic>Humans</topic><topic>Lynch syndrome</topic><topic>Male</topic><topic>Middle Aged</topic><topic>MLH1</topic><topic>Models, Molecular</topic><topic>Mutation</topic><topic>MutL Protein Homolog 1</topic><topic>Nuclear Proteins - chemistry</topic><topic>Nuclear Proteins - genetics</topic><topic>Nuclear Proteins - metabolism</topic><topic>Pedigree</topic><topic>Protein Conformation</topic><topic>Protein Interaction Domains and Motifs</topic><topic>Tumors</topic><topic>variants of unknown significance</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Pineda, M.</creatorcontrib><creatorcontrib>González-Acosta, M.</creatorcontrib><creatorcontrib>Thompson, B.A.</creatorcontrib><creatorcontrib>Sánchez, R.</creatorcontrib><creatorcontrib>Gómez, C.</creatorcontrib><creatorcontrib>Martínez-López, J.</creatorcontrib><creatorcontrib>Perea, J.</creatorcontrib><creatorcontrib>Caldés, T.</creatorcontrib><creatorcontrib>Rodríguez, Y.</creatorcontrib><creatorcontrib>Landolfi, S.</creatorcontrib><creatorcontrib>Balmaña, J.</creatorcontrib><creatorcontrib>Lázaro, C.</creatorcontrib><creatorcontrib>Robles, L.</creatorcontrib><creatorcontrib>Capellá, G.</creatorcontrib><creatorcontrib>Rueda, D.</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>Neurosciences Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Clinical genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Pineda, M.</au><au>González-Acosta, M.</au><au>Thompson, B.A.</au><au>Sánchez, R.</au><au>Gómez, C.</au><au>Martínez-López, J.</au><au>Perea, J.</au><au>Caldés, T.</au><au>Rodríguez, Y.</au><au>Landolfi, S.</au><au>Balmaña, J.</au><au>Lázaro, C.</au><au>Robles, L.</au><au>Capellá, G.</au><au>Rueda, D.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Detailed characterization of MLH1 p.D41H and p.N710D variants coexisting in a Lynch syndrome family with conserved MLH1 expression tumors</atitle><jtitle>Clinical genetics</jtitle><addtitle>Clin Genet</addtitle><date>2015-06</date><risdate>2015</risdate><volume>87</volume><issue>6</issue><spage>543</spage><epage>548</epage><pages>543-548</pages><issn>0009-9163</issn><eissn>1399-0004</eissn><abstract>Lynch syndrome (LS) is an autosomal dominant cancer‐susceptibility disease caused by inactivating germline mutations in mismatch repair (MMR) genes. Variants of unknown significance (VUS) are often detected in mutational analysis of MMR genes. Here we describe a large family fulfilling Amsterdam I criteria carrying two rare VUS in the MLH1 gene: c.121G > C (p.D41H) and c.2128A > G (p.N710D). Collection of clinico‐pathological data, multifactorial analysis, in silico predictions, and functional analyses were used to elucidate the clinical significance of the identified MLH1 VUS. Only the c.121G > C variant cosegregated with LS‐associated tumors in the family. Diagnosed colorectal tumors were microsatellite unstable although immunohistochemical staining revealed no loss of MMR proteins expression. Multifactorial likelihood analysis classified c.2128A > G as a non‐pathogenic variant and c.121G > C as pathogenic. In vitro functional tests revealed impaired MMR activity and diminished expression of c.121G > C. Accordingly, the N710 residue is located in the unconserved MLH1 C‐terminal domain, whereas D41 is highly conserved and located in the ATPase domain. The obtained results will enable adequate genetic counseling of c.121G > C and c.2128A > G variant carriers and their families. Furthermore, they exemplify how cumulative data and comprehensive analyses are mandatory to refine the classification of MMR variants.</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>25060679</pmid><doi>10.1111/cge.12467</doi><tpages>6</tpages><orcidid>https://orcid.org/0000-0001-8655-1839</orcidid></addata></record> |
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| subjects | Adaptor Proteins, Signal Transducing - chemistry Adaptor Proteins, Signal Transducing - genetics Adaptor Proteins, Signal Transducing - metabolism Adult Age of Onset Amino Acid Substitution Binding Sites Codon Colorectal Neoplasms, Hereditary Nonpolyposis - diagnosis Colorectal Neoplasms, Hereditary Nonpolyposis - genetics Family Female Gene Expression Genetic counseling Genetic disorders Genetic Variation Heterozygote HNPCC Humans Lynch syndrome Male Middle Aged MLH1 Models, Molecular Mutation MutL Protein Homolog 1 Nuclear Proteins - chemistry Nuclear Proteins - genetics Nuclear Proteins - metabolism Pedigree Protein Conformation Protein Interaction Domains and Motifs Tumors variants of unknown significance |
| title | Detailed characterization of MLH1 p.D41H and p.N710D variants coexisting in a Lynch syndrome family with conserved MLH1 expression tumors |
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