Evaluation of <i>MLH1</i> variants of unclear significance

Köger, Nicole; Paulsen, Lea; López-Köstner, Francisco; Valle, Adriana Della; Vaccaro, Carlos; Palmero, Edenir Inêz; Sarroca, Carlos; Neffa, Florencia; Kalfayan, Pablo; González, María Laura; Rossi, Benedito Mauro; Reis, Rui Manuel; Brieger, Angela; Zeuzem, Stefan; Hinrichsen, Inga; Dominguez‐Valentin, Mev; Plotz, Guido

doi:10.1002/gcc.22536

Cited by 12 publications

(14 citation statements)

References 45 publications

(93 reference statements)

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“…MutLα heterodimer is responsible for directing the downstream MMR events. Any change in upstream or downstream MMR events can cause mismatched DNA which disturbs ATPase activity and results in a distinct conformational change that is crucial for mismatch repairing [13]. Rather than clinical diagnosis likely for LS like mCRC, a confirmed genetic mutation in one of known MMR genes (MLH1, MSH2, MSH6, PMS2 and EPCAM) should be present for the diagnosis of LS [14].…”

Section: Introductionmentioning

confidence: 99%

Combinatorial approach of in silico and in vitro evaluation of MLH1 variant associated with Lynch syndrome like metastatic colorectal cancer

Saleem

Zaib

et al. 2020

Bioscience Reports

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Colorectal cancer (CRC) is the third most developing cancer worldwide and Lynch syndrome (LS) accounts for 3–4% of CRC. Genetic alteration in any of DNA mismatch repair (MMR) gene is the major cause of LS that disrupt the normal upstream and downstream MMR events. Germline mutation of MLH1 in heterozygous state have an increased risk for CRC. Defective MMR pathway mostly results in microsatellite instability (MSI) that occurs in high percentage of CRC associated tumors. Here, we reported a patient with LS like metastatic CRC (mCRC) associated with other related cancers. Whole exome sequencing (WES) of the proband was performed to identify potential causative gene. Genetic screening validated by Sanger sequencing identified a heterozygous missense mutation in exon 12 of MLH1 (c.1151T>A, p.V384D). The clinical significance of identified variant was elucidated on the basis of clinicopathological data, computational predictions and various in vitro functional analysis. In silico predictions classified the variant to be deleterious and evolutionary conserved. In vitro functional studies revealed a significant decrease in protein expression because of stability defect leading to loss of MMR activity. Mutant residue found in MutL transducer domain of MLH1 that localized in the nucleus but translocation was not found to be significantly disturbed. In conclusion, our study give insight into reliability of combinatorial prediction approach of in silico and in vitro expression analysis. Hence, we highlighted the pathogenic correlation of MLH1 variant with LS associated CRC as well as help in earlier diagnosis and surveillance for improved management and genetic counselling.

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Section: Introductionmentioning

confidence: 99%

Combinatorial approach of in silico and in vitro evaluation of MLH1 variant associated with Lynch syndrome like metastatic colorectal cancer

Saleem

Zaib

et al. 2020

Bioscience Reports

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“…Complete cosegregation of the variant with the disease was evident in this family, which is the most reliable way to evaluate the pathogenicity of a variant [21]. All patients (II-15, III-4, III-28, and III-33) carried the MLH1 missense variant, including two unaffected members (III-32, III-35).…”

Section: Discussionmentioning

confidence: 78%

Functional Characterization of a Missense Variant of MLH1 Identified in Lynch Syndrome Pedigree

et al. 2020

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Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRCs) inherited in an autosomal-dominant manner. Here, we reported a multigeneration Chinese family clinically diagnosed with LS according to the Amsterdam II criteria. To identify the underlying causative gene for LS in this family, whole-exome sequencing (WES) was performed. A germline missense variant (c.2054C>T:p.S685F) in exon 18 of MLH1 was successfully identified by WES. Sanger sequencing verified the results of WES and also confirmed the cosegregation of the MLH1 missense variant in all affected members of the family including two unaffected family members. Bioinformatic tools predicted the identified MLH1 variant as deleterious. Immunohistochemistry (IHC) staining showed loss of MLH1 and PMS2 protein expression. In vitro expression analysis also revealed that the identified MLH1 missense variant (c.2054C>T:p.S685F) results in reduced expression of both MLH1 and PMS2 proteins. Based on the American College of Medical Genetics and Genomics (ACMG) guidelines, the missense mutation c.2054C>T in MLH1 was classified as a “pathogenic” variant. Two unaffected family members were later recommended for colonoscopy and other important cancer diagnostic inspections every 1-2 years as both were at higher risk of LS. In conclusion, our findings widen the genotypic spectrum of MLH1 mutations responsible for LS. This study increases the phenotypic spectrum of LS which will certainly help the clinicians in diagnosing LS in multigeneration families. This study also puts emphasis on the importance of genetic counselling for the benefit of asymptomatic carriers of MMR gene variants who are at higher risk of LS.

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“…This whole process of network construction and research development on hereditary cancer in Latin America prepares the ground for global Latin American collaborations on increasing the knowledge of MMR variants in different populations and to bring additional awareness of this condition to medical professionals and public health leaders in this region. Since its inception, more than ten international scientific publications have been generated in hereditary CRC by our network . Furthermore, Argentina, Uruguay and Chile have initiated their participation on the PLSD, providing information of a total of 128 prospective path_MMR carriers to enrich the global database of variation.…”

Section: Latin American Hereditary Crc Collaborative Research Networkmentioning

confidence: 99%

From colorectal cancer pattern to the characterization of individuals at risk: Picture for genetic research in Latin America

Vaccaro

López-Köstner

Adriana

et al. 2018

Intl Journal of Cancer

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Colorectal cancer (CRC) is one of the most common cancers in Latin America and the Caribbean, with the highest rates reported for Uruguay, Brazil and Argentina. We provide a global snapshot of the CRC patterns, how screening is performed, and compared/contrasted to the genetic profile of Lynch syndrome (LS) in the region. From the literature, we find that only nine (20%) of the Latin America and the Caribbean countries have developed guidelines for early detection of CRC, and also with a low adherence. We describe a genetic profile of LS, including a total of 2,685 suspected families, where confirmed LS ranged from 8% in Uruguay and Argentina to 60% in Peru. Among confirmed LS, path_MLH1 variants were most commonly identified in Peru (82%), Mexico (80%), Chile (60%), and path_MSH2/EPCAM variants were most frequently identified in Colombia (80%) and Argentina (47%). Path_MSH6 and path_PMS2 variants were less common, but they showed important presence in Brazil (15%) and Chile (10%), respectively. Important differences exist at identifying LS families in Latin American countries, where the spectrum of path_MLH1 and path_MSH2 variants are those most frequently identified. Our findings have an impact on the evaluation of the patients and their relatives at risk for LS, derived from the gene affected. Although the awareness of hereditary cancer and genetic testing has improved in the last decade, it is remains deficient, with 39%–80% of the families not being identified for LS among those who actually met both the clinical criteria for LS and showed MMR deficiency.

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Evaluation of MLH1 variants of unclear significance

Cited by 12 publications

References 45 publications

Combinatorial approach of in silico and in vitro evaluation of MLH1 variant associated with Lynch syndrome like metastatic colorectal cancer

Combinatorial approach of in silico and in vitro evaluation of MLH1 variant associated with Lynch syndrome like metastatic colorectal cancer

Functional Characterization of a Missense Variant of MLH1 Identified in Lynch Syndrome Pedigree

From colorectal cancer pattern to the characterization of individuals at risk: Picture for genetic research in Latin America

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