Mutations in Non-MMR Genes Modifying or Mimicking Lynch Syndrome Phenotype

2013 ◽  
pp. 135-169
Author(s):  
Mala Pande ◽  
Jinyun Chen ◽  
Chongjuan Wei ◽  
Yu-Jing Huang ◽  
Marsha L. Frazier
Keyword(s):  
Lynch Syndrome ◽  
Mmr Genes

scholarly journals A rare large duplication of MLH1 identified in Lynch syndrome

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Abhishek Kumar ◽  
Nagarajan Paramasivam ◽  
Obul Reddy Bandapalli ◽  
Matthias Schlesner ◽  
Tianhui Chen ◽  
...  
Keyword(s):  
Amino Acid ◽  
Lynch Syndrome ◽  
Splice Site ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Splice Donor Site ◽  
Laboratory Diagnostics ◽  
Mmr Genes ◽  
Base Pair Deletion ◽  
Splice Site Variant

Abstract Background The most frequently identified strong cancer predisposition mutations for colorectal cancer (CRC) are those in the mismatch repair (MMR) genes in Lynch syndrome. Laboratory diagnostics include testing tumors for immunohistochemical staining (IHC) of the Lynch syndrome-associated DNA MMR proteins and/or for microsatellite instability (MSI) followed by sequencing or other techniques, such as denaturing high performance liquid chromatography (DHPLC), to identify the mutation. Methods In an ongoing project focusing on finding Mendelian cancer syndromes we applied whole-exome/whole-genome sequencing (WES/WGS) to 19 CRC families. Results Three families were identified with a pathogenic/likely pathogenic germline variant in a MMR gene that had previously tested negative in DHPLC gene variant screening. All families had a history of CRC in several family members across multiple generations. Tumor analysis showed loss of the MMR protein IHC staining corresponding to the mutated genes, as well as MSI. In family A, a structural variant, a duplication of exons 4 to 13, was identified in MLH1. The duplication was predicted to lead to a frameshift at amino acid 520 and a premature stop codon at amino acid 539. In family B, a 1 base pair deletion was found in MLH1, resulting in a frameshift and a stop codon at amino acid 491. In family C, we identified a splice site variant in MSH2, which was predicted to lead loss of a splice donor site. Conclusions We identified altogether three pathogenic/likely pathogenic variants in the MMR genes in three of the 19 sequenced families. The MLH1 variants, a duplication of exons 4 to 13 and a frameshift variant, were novel, based on the InSiGHT and ClinVar databases; the MSH2 splice site variant was reported by a single submitter in ClinVar. As a variant class, duplications have rarely been reported in the MMR gene literature, particularly those covering several exons.

SVA retrotransposon insertion in exon of MMR genes results in aberrant RNA splicing and causes Lynch syndrome

2020 ◽  
Author(s):  
Gou Yamamoto ◽  
Izumi Miyabe ◽  
Keisuke Tanaka ◽  
Miho Kakuta ◽  
Motoko Watanabe ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Rna Splicing ◽  
Mmr Genes ◽  
Retrotransposon Insertion ◽  
Aberrant Rna

Overlooking MMR deficiency in carriers of certain pathogenic variants by routine MSI and/or IHC testing in Lynch syndrome: Implications for a wider MMR deficiency testing.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16107-e16107
Author(s):  
Marija Staninova Stojovska ◽  
Katerina Kubelka Sabit ◽  
Dzengis Jasar ◽  
Rubens Jovanovic ◽  
Nadica Matevska ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Positive Result ◽  
Splice Site Mutation ◽  
The Other ◽  
Sporadic Colorectal Cancer ◽  
Site Mutation ◽  
Potential Implication ◽  
Mmr Genes ◽  
Pathogenic Variants ◽  
Mmr Deficiency

e16107 Background: DNA mismatch repair (MMR) deficiency occurs in both inherited/sporadic colorectal cancer (CRC) and endometrial cancer, but it may also be found in some other types of cancer. At present, MMR status testing in clinical practice is recommended for all CRC patients in order to identify those who should be offered genetic testing for the Lynch syndrome (LS), inform disease prognosis, and guide therapeutic management.There are two commonly accepted methods for MMR deficiency analysis, one based on the detection of microsatellite instability (MSI) by PCR and the other based on the detection of protein expression of the MMR genes using immunohistochemistry (IHC). The objective of this study was to evaluate the concordance between IHC and MSI in tumors from 18 LS patients with known pathogenic germline variants in MMR genes (MLH1, MSH2, PMS2 and MSH6). Methods: The MSI testing was performed using the five gene Bethesda panel (BAT25, BAT26, D2S123, D5S346, D17S250) while the IHC testing was done with the use of a standard 4 antibody panel (MLH1, MSH2, PMS2 and MSH6). Results: High concordance of the two methods was observed in 13/18 (72.2%) patients, mainly with disruptive mutations in the МLH1, MSH2 and PMS2 genes. Inconsistent results were obtained in 5/18 (28.8%) patients, of whom two had a positive result only with the use of the PCR method [carriers of MLH1 c.62C > T (p.Ala21Val) and c.244A > G (p.Thr82Ala) missense variants], other two had a positive result only with IHC [carriers of MSH6 c.3514dupA (p.Arg1172LysfsTer5) and c.2384T > C (p.Ile795Thr)] and one patient had normal results using both methods (carrier of MSH6 c.457+1G > T splice site mutation that results in exon 3 skipping). A positive predictive value of either MSI or IHC used as a single methods for screening was 83.3%, which indicates that a substantial number of cases with MMR tumors can be misdiagnosed by using only either one or the other of these two methods. Conclusions: These results have a potential implication not only for LS screening in CRC patients, but also for the detection of the MMR deficiency in patients with various tumors that might benefit from the checkpoint inhibitor immunotherapy. The use of extended MSI NGS panels might provide a higher sensitivity for the detection of MMR deficiency compared to the standard MSI or ICH testing.

A new strategy to screen MMR genes in Lynch Syndrome: HA-CAE, MLPA and RT-PCR

2009 ◽  
Vol 45 (8) ◽  
pp. 1485-1493 ◽  
Author(s):  
Lucia Perez-Cabornero ◽  
Eladio Velasco ◽  
Mar Infante ◽  
David Sanz ◽  
Enrique Lastra ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Rt Pcr ◽  
Mmr Genes ◽  
New Strategy

scholarly journals Insertion of an SVA Element in MSH2 as a Novel Cause of Lynch Syndrome

2020 ◽  
Author(s):  
Ciyu Yang ◽  
Yirong Li ◽  
Magan Trottier ◽  
Michael Farrell ◽  
Vikas Rai ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Pcr Analysis ◽  
Rt Pcr ◽  
Dna Mismatch ◽  
Mmr Genes ◽  
Antisense Orientation ◽  
The Family ◽  
Long Range Pcr ◽  
Early Onset Colorectal Cancer ◽  
Generation Sequencing

Germline mutations in the DNA mismatch repair (MMR) genes cause Lynch syndrome (LS). Insertions of retrotransposons in MMR genes have been reported as a rare cause of LS. Here, we present a novel SINE-VNTR-Alu (SVA) insertion in exon 12 of MSH2 in an individual with early-onset colorectal cancer and strong LS family history. RT-PCR analysis indicated a larger aberrant MSH2 transcript in one of the family members. MSK-IMPACT next-generation sequencing testing and long-range PCR revealed an insertion in MSH2 exon 12 at the c.1972 position in an antisense orientation. The insertion was further characterized as an SVA element approximately 3 kb in length, belonging to the SVA_F1 family of retrotransposons.

Genetic identification and characterization of Lynch syndrome in a multi-ethnic biobank.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 1520-1520
Author(s):  
Rachel Rosenblum ◽  
Sabrina A. Suckiel ◽  
Gillian M. Belbin ◽  
Sinead Cullina ◽  
Judy H. Cho ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Diagnostic Criteria ◽  
Sequence Data ◽  
Genetic Identification ◽  
European Ancestry ◽  
Gene Variants ◽  
Loss Of Function ◽  
Mmr Genes ◽  
Pathogenic Variants ◽  
Increased Risk

1520 Background: Lynch syndrome (LS), caused by germline pathogenic variants in mismatch repair (MMR) genes, results in increased risk of colorectal, endometrial, and other cancers. LS has a prevalence of ~1 in 440 in European ancestry populations; prevalence data in other populations are limited. We identified and characterized carriers of pathogenic MMR gene variants in the multi-ethnic Bio Me Biobank in New York City. Methods: Exome sequence data from ~31,000 Bio Me participants were evaluated for known (per ClinVar) and predicted (loss-of-function) pathogenic variants in MMR genes. Population groups were defined by genetic ancestry. Participant questionnaires and electronic health records (EHRs) of carriers were reviewed for personal or family history of malignancy. Results: We identified 48 carriers of 33 distinct pathogenic variants in PMS2 (48%), MLH1 (27%), MSH6 (15%), and MSH2 (10%), for an estimated prevalence of ~1/640 in the Bio Me Biobank. Prevalence was higher among individuals of Non-Jewish European (N = 14; 1/400) and African (N = 14; 1/490) ancestries, compared to Puerto Rican (N = 8; 1/640), Ashkenazi Jewish (N = 6; 1/690), and other/mixed (N = 6) ancestries. Carriers had a median age of 56 (range 27 to 77) years and were 50% female. Overall rate of malignancy among carriers was 38%, with the lowest rate in PMS2 (26%) and the highest rate in MSH6 (57%) variant carriers. We found a high prevalence of endometrial cancer (21% of female carriers) and a lower prevalence of colorectal cancer (4% of all carriers). Only 2 carriers (4%) had a diagnosis of LS in their EHRs, and only 1 carrier met Amsterdam diagnostic criteria for LS. Conclusions: These data show that ~0.15% of participants in a multi-ethnic biobank are carriers of pathogenic MMR gene variants and suggest that the prevalence is higher in European and lower in non-European ancestry populations. Notably, most carriers do not have a clinical diagnosis of LS and do not meet diagnostic criteria for LS. Carriers demonstrate variable rates of cancer, which may contribute to under-diagnosis of LS. Genomic screening for pathogenic MMR variants may lead to earlier diagnosis of LS and improved outcomes.

scholarly journals Lynch syndrome I: A case report

2008 ◽  
Vol 61 (1-2) ◽  
pp. 79-82
Author(s):  
Vesna Zivkovic ◽  
Vuka Katic ◽  
Jasmina Gligorijevic ◽  
Zlatibor Andjelkovic ◽  
Aleksandar Petrovic ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Case Report ◽  
Lynch Syndrome ◽  
Microsatellite Instability ◽  
Clinical Stage ◽  
Family Members ◽  
Advanced Rectal Cancer ◽  
Degree Relative ◽  
Mmr Genes ◽  
Amsterdam Criteria

Introduction. Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndromes J and II, accounts for about 5-8% of colorectal cancers. Lynch syndrome I is an autosomal domi?nant inherited disorder characterized by early onset of colorectal cancer, predominance of proximal and multiple tumors, and microsatellite instability. In order to identify HNPCC, the international "Amsterdam criteria" have been used. Case report. The proband was a 40-year-old male who was admitted to hospital with a diagnosis of advanced rectal cancer. Left colectomy was carried out. A histopathologic diagnosis of poorly differentiated adenocarcinoma of clinical stage Dukes C was made. The family talking was done and it was revealed that the pro-band had five family members (one of first degree relative) with colorectal cancer, and two successive generations affected. All malignancy were diagnosed before 45 years of age. In one family member, metachronous transverse cancer was revealed 12 years after surgery for cecal adenocarcinoma. Discussion and conclusion. The main molecular cause for HNPCC is constitutional mutation in one of the mismatch repair (MMR) genes that regulate the excision of errors occurring during DNA replication. The most often are mutations of MLHI and MSH2 genes, and microsatellite instability is present in about 90-95% HNPCC. In this report, we present a case of an HNPCC patient who met the Amsterdam criteria for Lynch syndrome I. Family members that fulfill the Amsterdam criteria should be investigated for mutation in MMR genes. The genetic tests are not routinely available, so colonoscopic screening of all asymptomatic family members older than 25 has been recommended.

scholarly journals Novel Implications in Molecular Diagnosis of Lynch Syndrome

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Raffaella Liccardo ◽  
Marina De Rosa ◽  
Paola Izzo ◽  
Francesca Duraturo
Keyword(s):  
Lynch Syndrome ◽  
Clinical Manifestations ◽  
Mendelian Inheritance ◽  
Dna Mismatch ◽  
Variants Of Unknown Significance ◽  
Mmr Genes ◽  
Risk Alleles ◽  
Detection Analysis ◽  
Unknown Significance ◽  
Analytical Strategies

About 10% of total colorectal cancers are associated with known Mendelian inheritance, as Familial Adenomatous Polyposis (FAP) and Lynch syndrome (LS). In these cancer types the clinical manifestations of disease are due to mutations in high-risk alleles, with a penetrance at least of 70%. The LS is associated with germline mutations in the DNA mismatch repair (MMR) genes. However, the mutation detection analysis of these genes does not always provide informative results for genetic counseling of LS patients. Very often, the molecular analysis reveals the presence of variants of unknown significance (VUSs) whose interpretation is not easy and requires the combination of different analytical strategies to get a proper assessment of their pathogenicity. In some cases, these VUSs may make a more substantial overall contribution to cancer risk than the well-assessed severe Mendelian variants. Moreover, it could also be possible that the simultaneous presence of these genetic variants in several MMR genes that behave as low risk alleles might contribute in a cooperative manner to increase the risk of hereditary cancer. In this paper, through a review of the recent literature, we have speculated a novel inheritance model in the Lynch syndrome; this could pave the way toward new diagnostic perspectives.

scholarly journals Sanger sequencing of MMR genes in a one-plate system

2018 ◽  
Vol 26 (2) ◽  
pp. 153-163
Author(s):  
Lucian Negura ◽  
Anca Negura
Keyword(s):  
Colorectal Cancer ◽  
Lynch Syndrome ◽  
Sanger Sequencing ◽  
Germ Line ◽  
Cost Effective ◽  
Complete Analysis ◽  
Continuous Increase ◽  
Technical Problems ◽  
Mmr Genes ◽  
Incidence And Mortality

Abstract Both incidence and mortality of colorectal cancer (CRC) in Romania have shown a continuous increase during the last decades. Hereditary Non-Polyposic Colorectal Cancer (HNPCC), also known as Lynch syndrome, is mainly attributable to mismatch repair (MMR) genes MSH2, MSH6, and MLH1. Individuals carrying germ-line mutations of these genes present high lifetime risk of colorectal and other cancers, compared to non-carriers. Oncogenetics is developed worldwide nowadays, for identifying hereditary predisposition to cancer and offering appropriate clinical follow-up to patients and mutation carriers in Lynch families. Molecular oncogenetic diagnosis in Lynch syndrome is based on complete Sanger sequencing of entire MMR genes, which is time and resources consuming, therefore needing an appropriate and adapted optimization. Conventional sequencing requires a sufficient number of available samples to be processed simultaneously, which increases the waiting time for diagnostic results. Complete analysis for only one patient meets difficult technical problems due to the complex co-amplification of all gene regions of interest within the same conditions, therefore increasing the costs and reducing the cost-effectiveness of the test. Here we present an original and robust technical protocol for sequencing the entire MSH2, MSH6, and MLH1 coding sequence for one patient in a single PCR plate. Our optimized and verified system overcomes all technical problems and offers a quick, robust, and cost-effective possibility to personalize molecular oncogenetic diagnosis in Lynch syndrome.

scholarly journals Clinical and genetic aspects of differential diagnostics of hereditary non-polyposis colorectal cancer

2019 ◽  
Vol 6 (2) ◽  
pp. 21-27
Author(s):  
A. V. Semyanikhina ◽  
A. O. Rasulov ◽  
L. N. Lyubchenko
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Lynch Syndrome ◽  
Mismatch Repair ◽  
Heterogeneous Group ◽  
Differential Diagnostics ◽  
Genetic Characteristics ◽  
Dna Mismatch ◽  
Mmr Genes ◽  
Long Time

Lynch syndrome was synonymous with hereditary non-polyposis colorectal cancer for a long time, however, mapping of the DNA mismatch repair (MMR) genes has led to distinguish Lynch syndrome as an independent syndromic unit from a number of Lynch-like syndromes that phenotypically mimic with the most frequent hereditary variant of colon cancer but genetically representing quite a heterogeneous group. This article presents up to date clinical and genetic characteristics of Lynch syndrome and Lynch-like conditions.

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