A database to support the interpretation of human mismatch repair gene variants

Ou, Jianghua; Niessen, Renée C.; Vonk, Jan J.; Westers, Helga; Hofstra, Robert; Sijmons, Rolf H.

doi:10.1002/humu.20907

Cited by 53 publications

(43 citation statements)

References 22 publications

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“…The probabilities calculated were then classified in five classes, following the guidelines of the Special Issue of Human Mutation. [3][4][5][6][7][8][9][10][11][12] An increasing number of groups are trying to classify UVs using these recommendations, but most of them focus on the BRCA1 and BRCA2 genes, for which a multifactorial likelihood classification has already been developed and refined. Instead, for MMR genes, there are not well-established models or well-characterized features 42 so that, at the time of writing, a very few groups have attempted to classify MMR UVs with the Bayesian likelihood method.…”

Section: Discussionmentioning

confidence: 43%

Integrated analysis of unclassified variants in mismatch repair genes

Pastrello

Marroni

et al. 2011

Genetics in Medicine

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Purpose: Lynch syndrome is a genetic disease that predisposes to colorectal tumors, caused by mutation in mismatch repair genes. The use of genetic tests to identify mutation carriers does not always give perfectly clear results, as happens when an unclassified variant is found. This study aimed to define the pathogenic role of 35 variants present in MSH2, MLH1, MSH6, and PMS2 genes identified in our 15-year case study. Methods: We collected clinical and molecular data of all carriers, and then we analyzed the variants pathogenic role with web tools and molecular analyses. Using a Bayesian approach, we derived a posterior probability of pathogenicity and classified each variant according to a standardized five-class system. Results: The MSH2 p.Pro349Arg, p.Met688Arg, the MLH1 p.Gly67Arg, p.Thr82Ala, p.Lys618Ala, the MSH6 p.Ala1236Pro, and the PMS2 p.Arg20Gln were classified as pathogenic, and the MSH2 p.Cys697Arg and the PMS2 p.Ser46Ile were classified as likely pathogenic. Seven variants were likely nonpathogenic, 3 were nonpathogenic, and 16 remained uncertain. Conclusion: Quantitative assessment of several parameters and their integration in a multifactorial likelihood model is the method of choice for classifying the variants. As such classifications can be associated with surveillance and testing recommendations, the results and the method developed in our study can be useful for helping laboratory geneticists in evaluation of genetic tests and clinicians in the management of carriers. Genet Med 2011:13(2):115-124.

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Section: Discussionmentioning

confidence: 43%

Integrated analysis of unclassified variants in mismatch repair genes

Pastrello

Marroni

et al. 2011

Genetics in Medicine

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“…The nine novel DNA variants were not detected in the 100 healthy controls (Table 2). To verify the pathogenicity of the novel variants, we used a combination of computational and segregation analyses, as described in our previous studies [7,21]. The results are shown in Table 2.…”

Section: Resultssupporting

confidence: 48%

“…As shown in Table 1, 27 germline variants were identified in MSH6, nine of which were novel variants not previously reported in the NCBI SNP database, the Human Gene Mutation Database (http://www.hgmd.cf.ac.uk/ac/index.php), the International Society for Gastrointestinal Hereditary Tumors (InSight; http://www.insightgroup.org/) or the MMR variants database [21]. MSI analysis was performed for all patients with available paraffin-embedded tumor tissues; these results are listed in Table 1.…”

Section: Resultsmentioning

confidence: 44%

Incomplete Segregation of <em>MSH6</em> Frameshift Variants with Phenotype of Lynch Syndrome

Liccardo

Rosa

Rossi

et al. 2017

Preprint

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Background: Lynch syndrome, the most frequent form of hereditary colorectal cancer and involves mutations in mismatch repair genes. The aim of this study was to identify mutations in MSH6 from 97 subjects negative for mutations in MLH1 and MSH2. Methods: By direct sequencing, we identified 27 MSH6 variants, of which, nine were novel. To verify the pathogenicity of these novel variants we performed in silico and segregation analyses. Results: Three novel variants were predicted by in silico analysis as damaging mutations and segregated with the disease phenotype. While, a novel frameshift deletion variant that was predicted to yield a premature stop codon, did not segregate with the LS phenotype in 3 of 4 cases in the family. Interestingly, another frame-shift variant identified in this study, already described in the literature, also did not segregate with the LS phenotype in 1 of 2 affected subjects in the family. In all affected subjects of both families, no mutation was detected in other MMR genes. Therefore, it is expected that within these families other genetic factors contribute to the disease either alone or in combination with MSH6 variants. Conclusion: We conclude that caution should be exercised in counseling for MSH6-associated LS family members.

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“…All articles mentioning MLH1 K618A listed in the InSIGHT mismatch repair gene variant database 8 and the Mismatch Repair Gene Unclassified Variant Database 8 were reviewed. A PubMed search yielded several additional references.…”

Section: Literature Reviewmentioning

confidence: 99%

“…Thus, the cancer susceptibility of individuals and families identified with MLH1 K618A is not understood. 8 In the present study, we evaluated more precisely the role of MLH1 K618A in predisposition to cancer. We genotyped 1512 control subjects to assess the frequency of this variant in the general population.…”

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confidence: 99%

The Germline MLH1 K618A Variant and Susceptibility to Lynch Syndrome-Associated Tumors

Medeiros

Lindor

Couch

et al. 2012

The Journal of Molecular Diagnostics

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Missense variants discovered during sequencing of cancer susceptibility genes can be problematic for clinical interpretation. MLH1 K618A, which results from a 2-bp alteration (AAG¡GCG) leading to a substitution of lysine to alanine in codon 618, has variously been interpreted as a pathogenic mutation, a variant of unknown significance, and a benign polymorphism. We evaluated the role of MLH1 K618A in predisposition to cancer by genotyping 1512 control subjects to assess its frequency in the general population. We also reviewed the literature concerning MLH1 K618A in families with colorectal cancer. The measured allele frequency of the K618A variant was 0.40%, which is remarkably close to the 0.44% summarized from 2491 control subjects in the literature. K618A was over-represented in families with suspected Lynch syndrome. In 1366 families, the allele frequency was 0.88% (OR ‫؍‬ 2.1, 95% CI ‫؍‬ 1.3 to 3.5; P ‫؍‬ 0.006). In studies of sporadic cancers of the type associated with Lynch syndrome, K618A was overrepresented in 1742 cases (allele frequency of 0.83) (OR ‫؍‬ 2.0, 95% CI ‫؍‬ 1.2 to 3.2; P ‫؍‬ 0.008). We conclude that MLH1 K618A is not a fully penetrant Lynch syndrome mutation, although it is not without effect, appearing to increase the risk of Lynch syndrome-associated tumors approximately twofold. Our systematic assessment approach may be useful for variants in other genes.

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A database to support the interpretation of human mismatch repair gene variants

Cited by 53 publications

References 22 publications

Integrated analysis of unclassified variants in mismatch repair genes

Integrated analysis of unclassified variants in mismatch repair genes

Incomplete Segregation of <em>MSH6</em> Frameshift Variants with Phenotype of Lynch Syndrome

The Germline MLH1 K618A Variant and Susceptibility to Lynch Syndrome-Associated Tumors

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