Gene: MLH1

Alternate names for this Gene: COCA2|FCC2|HNPCC|HNPCC2|MMRCS1|hMLH1

Gene Summary: The protein encoded by this gene can heterodimerize with mismatch repair endonuclease PMS2 to form MutL alpha, part of the DNA mismatch repair system. When MutL alpha is bound by MutS beta and some accessory proteins, the PMS2 subunit of MutL alpha introduces a single-strand break near DNA mismatches, providing an entry point for exonuclease degradation. The encoded protein is also involved in DNA damage signaling and can heterodimerize with DNA mismatch repair protein MLH3 to form MutL gamma, which is involved in meiosis. This gene was identified as a locus frequently mutated in hereditary nonpolyposis colon cancer (HNPCC).

Gene is located in Chromosome: 3

Location in Chromosome : 3p22.2

Description of this Gene: mutL homolog 1

Type of Gene: protein-coding

Gene: EPM2AIP1

Alternate names for this Gene: -

Gene Summary: The EPM2A gene, which encodes laforin, is mutated in an autosomal recessive form of adolescent progressive myoclonus epilepsy. The protein encoded by this gene binds to laforin, but its function is not known. This gene is intronless.

Gene is located in Chromosome: 3

Location in Chromosome : 3p22.2

Description of this Gene: EPM2A interacting protein 1

Type of Gene: protein-coding

rs367654552 in MLH1;EPM2AIP1 gene and Hereditary Non-Polyposis Colon Cancer Type 2 PMID 11748856 2001 Eight novel germline MLH1 and MSH2 mutations in hereditary non-polyposis colorectal cancer families from Spain.

PMID 9833759 1998 Excess of hMLH1 germline mutations in Swiss families with hereditary non-polyposis colorectal cancer.

PMID 9559627 1998 Germline mutations of hMLH1 and hMSH2 genes in patients with suspected hereditary nonpolyposis colorectal cancer and sporadic early-onset colorectal cancer.

PMID 11781295 2002 Functional analysis of hMLH1 variants and HNPCC-related mutations using a human expression system.

PMID 9326924 1997 A human compound heterozygote for two MLH1 missense mutations.

PMID 11793442 2002 Functional analysis of MLH1 mutations linked to hereditary nonpolyposis colon cancer.

PMID 9311737 1997 Hereditary nonpolyposis colorectal cancer families not complying with the Amsterdam criteria show extremely low frequency of mismatch-repair-gene mutations.

PMID 15365995 2004 Germline mutations in MLH1, MSH2 and MSH6 in Korean hereditary non-polyposis colorectal cancer families.

PMID 10375096 1999 Influence of selection criteria on mutation detection in patients with hereditary nonpolyposis colorectal cancer.

PMID 8872463 1996 Microsatellite instability and mutation analysis of hMSH2 and hMLH1 in patients with sporadic, familial and hereditary colorectal cancer.

PMID 10627141 1998 Four new mutations in the DNA mismatch repair gene MLH1 in colorectal cancers with microsatellite instability. Mutations in brief no. 157. Online.

PMID 11839723 2002 Pathogenicity of missense and splice site mutations in hMSH2 and hMLH1 mismatch repair genes: implications for genetic testing.

PMID 8571956 1996 Majority of hMLH1 mutations responsible for hereditary nonpolyposis colorectal cancer cluster at the exonic region 15-16.

PMID 8993976 1997 Characterization of MSH2 and MLH1 mutations in Italian families with hereditary nonpolyposis colorectal cancer.

PMID 22753075 2012 Functional characterization of MLH1 missense variants identified in Lynch syndrome patients.

PMID 20020535 2010 A cell-free assay for the functional analysis of variants of the mismatch repair protein MLH1.

PMID 8797773 1996 Germline mutations of hMLH1 and hMSH2 genes in Korean hereditary nonpolyposis colorectal cancer.

PMID 10413423 1999 Frequent microsatellite instability and mismatch repair gene mutations in young Chinese patients with colorectal cancer.

PMID 11726306 2001 Sixteen rare sequence variants of the hMLH1 and hMSH2 genes found in a cohort of 254 suspected HNPCC (hereditary non-polyposis colorectal cancer) patients: mutations or polymorphisms?

PMID 10598809 1999 Missense mutations in hMLH1 associated with colorectal cancer.

PMID 16083711 2005 Functional significance and clinical phenotype of nontruncating mismatch repair variants of MLH1.

PMID 21840485 2011 Dominantly inherited constitutional epigenetic silencing of MLH1 in a cancer-affected family is linked to a single nucleotide variant within the 5'UTR.

PMID 24084575 2014 The MLH1 c.-27C>A and c.85G>T variants are linked to dominantly inherited MLH1 epimutation and are borne on a European ancestral haplotype.

PMID 26888055 2016 Understanding the Pathogenicity of Noncoding Mismatch Repair Gene Promoter Variants in Lynch Syndrome.

PMID 22878509 2013 Identification of constitutional MLH1 epimutations and promoter variants in colorectal cancer patients from the Colon Cancer Family Registry.

PMID 21120944 2011 Verification of the three-step model in assessing the pathogenicity of mismatch repair gene variants.

PMID 27435373 2016 Comprehensive Mutation Analysis of PMS2 in a Large Cohort of Probands Suspected of Lynch Syndrome or Constitutional Mismatch Repair Deficiency Syndrome.

PMID 25711197 2015 Lynch Syndrome: A Primer for Urologists and Panel Recommendations.

PMID 25645574 2015 ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes.

PMID 25452455 2015 Hereditary colorectal cancer syndromes: American Society of Clinical Oncology Clinical Practice Guideline endorsement of the familial risk-colorectal cancer: European Society for Medical Oncology Clinical Practice Guidelines.

PMID 24493721 2014 American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers.

PMID 25356965 2015 ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing.

PMID 25070057 2014 Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-society Task Force on colorectal cancer.

PMID 25003300 2014 Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-Society Task Force on Colorectal Cancer.

PMID 27854360 2017 Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics.

PMID 23788249 2013 ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.

PMID 24310308 2014 ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis).

PMID 20065170 2010 American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility.

PMID 23408351 2013 Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts.

PMID 11598466 2001 Practice parameters for the identification and testing of patients at risk for dominantly inherited colorectal cancer--supporting documentation.

PMID 22167527 2012 Identification of individuals at risk for Lynch syndrome using targeted evaluations and genetic testing: National Society of Genetic Counselors and the Collaborative Group of the Americas on Inherited Colorectal Cancer joint practice guideline.

PMID 23535968 2013 Informing family members of individuals with Lynch syndrome: a guideline for clinical geneticists.

rs63749906 in MLH1;EPM2AIP1 gene and Hereditary Nonpolyposis Colorectal Cancer PMID 10082584 1999 Mutator phenotypes conferred by MLH1 overexpression and by heterozygosity for mlh1 mutations.

PMID 17440981 2007 Biallelic germline mutations of mismatch-repair genes: a possible cause for multiple pediatric malignancies.

PMID 16995940 2006 In silico and in vivo splicing analysis of MLH1 and MSH2 missense mutations shows exon- and tissue-specific effects.

PMID 17312306 2007 Lynch syndrome (hereditary nonpolyposis colorectal cancer) diagnostics.

PMID 17510385 2007 Functional analysis of human MLH1 variants using yeast and in vitro mismatch repair assays.

PMID 8521398 1995 Mutation screening in the hMLH1 gene in Swedish hereditary nonpolyposis colon cancer families.

PMID 12810663 2003 A yeast two-hybrid assay provides a simple way to evaluate the vast majority of hMLH1 germ-line mutations.

PMID 15731775 2005 Loss of mismatch repair protein immunostaining in colorectal adenomas from patients with hereditary nonpolyposis colorectal cancer.

rs587779001 in MLH1;EPM2AIP1 gene and Hereditary Nonpolyposis Colorectal Neoplasms PMID 21840485 2011 Dominantly inherited constitutional epigenetic silencing of MLH1 in a cancer-affected family is linked to a single nucleotide variant within the 5'UTR.

PMID 24084575 2014 The MLH1 c.-27C>A and c.85G>T variants are linked to dominantly inherited MLH1 epimutation and are borne on a European ancestral haplotype.

PMID 21404117 2011 Missense variants in hMLH1 identified in patients from the German HNPCC consortium and functional studies.

rs587779001 in MLH1;EPM2AIP1 gene and Neoplastic Syndromes, Hereditary PMID 29472279 2018 Comprehensive analysis of the MLH1 promoter region in 480 patients with colorectal cancer and 1150 controls reveals new variants including one with a heritable constitutional MLH1 epimutation.

PMID 22878509 2013 Identification of constitutional MLH1 epimutations and promoter variants in colorectal cancer patients from the Colon Cancer Family Registry.

PMID 21840485 2011 Dominantly inherited constitutional epigenetic silencing of MLH1 in a cancer-affected family is linked to a single nucleotide variant within the 5'UTR.

PMID 24084575 2014 The MLH1 c.-27C>A and c.85G>T variants are linked to dominantly inherited MLH1 epimutation and are borne on a European ancestral haplotype.

PMID 22453149 2012 Novel germline MLH1 and MSH2 mutations in Latvian Lynch syndrome families.

PMID 19224586 2009 Quantitative PCR high-resolution melting (qPCR-HRM) curve analysis, a new approach to simultaneously screen point mutations and large rearrangements: application to MLH1 germline mutations in Lynch syndrome.

PMID 24362816 2014 Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database.

PMID 10734316 2000 Microsatellite instability and the PTEN1 gene mutation in a subset of early onset gliomas carrying germline mutation or promoter methylation of the hMLH1 gene.

PMID 21642682 2011 Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome.

PMID 20704743 2010 A novel pathogenic MLH1 missense mutation, c.112A > C, p.Asn38His, in six families with Lynch syndrome.

PMID 22949379 2013 A multifactorial likelihood model for MMR gene variant classification incorporating probabilities based on sequence bioinformatics and tumor characteristics: a report from the Colon Cancer Family Registry.

PMID 12373605 2002 Genomic deletions of MSH2 and MLH1 in colorectal cancer families detected by a novel mutation detection approach.

PMID 22949387 2013 Calibration of multiple in silico tools for predicting pathogenicity of mismatch repair gene missense substitutions.

PMID 25345868 2015 Mismatch repair genes founder mutations and cancer susceptibility in Lynch syndrome.

PMID 17510385 2007 Functional analysis of human MLH1 variants using yeast and in vitro mismatch repair assays.

PMID 17594722 2007 Functional analysis helps to clarify the clinical importance of unclassified variants in DNA mismatch repair genes.

PMID 12658575 2003 Molecular analysis of hereditary nonpolyposis colorectal cancer in the United States: high mutation detection rate among clinically selected families and characterization of an American founder genomic deletion of the MSH2 gene.

PMID 16083711 2005 Functional significance and clinical phenotype of nontruncating mismatch repair variants of MLH1.

PMID 21120944 2011 Verification of the three-step model in assessing the pathogenicity of mismatch repair gene variants.