ClinVar Genomic variation as it relates to human health
NM_000249.4(MLH1):c.245C>T (p.Thr82Ile)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000249.4(MLH1):c.245C>T (p.Thr82Ile)
Variation ID: 90118 Accession: VCV000090118.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 37000992 (GRCh38) [ NCBI UCSC ] 3: 37042483 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Mar 24, 2015 May 1, 2024 Sep 5, 2013 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- T82I
- Other names
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- Canonical SPDI
- NC_000003.12:37000991:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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MLH1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
5624 | 5679 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
reviewed by expert panel
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Sep 5, 2013 | RCV000075604.5 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Sep 16, 2021 | RCV000222555.7 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 7, 2022 | RCV000659867.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 16, 2023 | RCV000630024.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 4, 2021 | RCV001778703.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 7, 2022 | RCV003477470.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Sep 05, 2013)
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reviewed by expert panel
Method: research
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Lynch Syndrome
Affected status: unknown
Allele origin:
germline
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International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
Accession: SCV000106601.3
First in ClinVar: Dec 19, 2013 Last updated: Dec 24, 2022
Comment:
Classified with v1.9 guidelines: https://docs.google.com/file/d/0B3JL6rP6JzhoN2EydHRVMEI1UGs
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Comment:
Multifactorial likelihood analysis posterior probability >0.99
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Pathogenic
(Sep 16, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000275627.7
First in ClinVar: May 29, 2016 Last updated: May 01, 2024 |
Comment:
The p.T82I pathogenic mutation (also known as c.245C>T), located in coding exon 3 of the MLH1 gene, results from a C to T substitution at … (more)
The p.T82I pathogenic mutation (also known as c.245C>T), located in coding exon 3 of the MLH1 gene, results from a C to T substitution at nucleotide position 245. The threonine at codon 82 is replaced by isoleucine, an amino acid with similar properties. This mutation has been identified in multiple HNPCC/Lynch syndrome families meeting Amsterdam I/II criteria (Syngal S et al. JAMA. 1999 Jul;282(3):247-53; Sjursen W et al. J. Med. Genet. 2010 Sep;47(9):579-85; Ambry internal data). Additionally, functional studies have demonstrated that this alteration leads to a loss of function (Syngal S et al. JAMA. 1999 Jul;282(3):247-53) and reduced repair activity and expression compared to wild-type (Hinrichsen I et al. Clin. Cancer Res. 2013 May;19(9):2432-41). In another study, expression of the variant protein was normal (>75%), but p.T82I showed a dominant negative mutator effect in one of the yeast assays with in vitro MMR activity of 27.2%. This particular mutation is located in a residue thought to be critical for ATP binding and other variants around the pocket were also shown to affect both dominant mutator effect and in vitro MMR activity (Takahashi M et al. Cancer Res. 2007 May;67(10):4595-604). Lastly, this alteration has been classified as pathogenic by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Thompson B et al. Nat. Genet. 2014 Feb;46(2):107-15; available at [www.insight-group.org/variants/classifications/]). Based on the available evidence, this alteration is classified as a pathogenic mutation. (less)
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Likely pathogenic
(Nov 01, 2016)
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criteria provided, single submitter
Method: clinical testing
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Colorectal cancer, hereditary nonpolyposis, type 2
Affected status: yes
Allele origin:
germline
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Center for Human Genetics, Inc, Center for Human Genetics, Inc
Accession: SCV000781750.1
First in ClinVar: Jul 09, 2018 Last updated: Jul 09, 2018 |
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Pathogenic
(Oct 04, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hereditary nonpolyposis colon cancer
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000917647.2
First in ClinVar: Nov 20, 2021 Last updated: Nov 20, 2021 |
Comment:
Variant summary: MLH1 c.245C>T (p.Thr82Ile) results in a non-conservative amino acid change located in the N-terminal domain (IPR002099) of the encoded protein sequence. Five of … (more)
Variant summary: MLH1 c.245C>T (p.Thr82Ile) results in a non-conservative amino acid change located in the N-terminal domain (IPR002099) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251394 control chromosomes (gnomAD). c.245C>T has been reported in the literature in multiple individuals affected with Lynch Syndrome (Syngal_1999, Sjursen_2010, Guindalini_2015, Sarode_2019, Li_2020). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant resulted in decreased MMR activity (Takahashi 2007, Hinrichsen 2013). Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as pathogenic (n=1) / likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Jan 14, 2020)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV001340976.2
First in ClinVar: Mar 25, 2020 Last updated: Jan 12, 2022 |
Comment:
This missense variant replaces threonine with isoleucine at codon 82 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces threonine with isoleucine at codon 82 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies have shown that this variant causes a significant decrease in mismatch repair activity (PMID: 17510385, 23403630). This variant has been reported in individuals affected with affected with Lynch syndrome (PMID: 10422993) or suspected of having Lynch syndrome (PMID: 19690142, 28514183). This variant has been shown to segregate with disease in six related individuals in a family (PMID: 20587412). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
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Likely pathogenic
(Jan 07, 2022)
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criteria provided, single submitter
Method: clinical testing
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Colorectal cancer, hereditary nonpolyposis, type 2
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004193062.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Oct 07, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV004220879.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
This missense variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in multiple individuals … (more)
This missense variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in multiple individuals with Lynch syndrome (PMID:1042293 (1999), PMID:17510385 (2007), PMID:19690412 (2010), PMID:26248088 (2015), PMID:30917047 (2019)). The variant has also been reported to decrease protein function in vitro (PMID:23403630 (2013)).Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. (less)
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Pathogenic
(Aug 16, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary nonpolyposis colorectal neoplasms
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000750980.6
First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Thr82Ala amino acid residue in MLH1. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Thr82Ala amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21239990, 21404117, 22736432, 26300997, 28514183). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects MLH1 function (PMID: 17510385, 23403630). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MLH1 protein function. ClinVar contains an entry for this variant (Variation ID: 90118). This missense change has been observed in individual(s) with Lynch syndrome (PMID: 10422993, 19690142, 20587412, 28514183). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 82 of the MLH1 protein (p.Thr82Ile). (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Tumour characteristics provide evidence for germline mismatch repair missense variant pathogenicity. | Li S | Journal of medical genetics | 2020 | PMID: 31391288 |
Screening for Lynch Syndrome by Immunohistochemistry of Mismatch Repair Proteins: Significance of Indeterminate Result and Correlation With Mutational Studies. | Sarode VR | Archives of pathology & laboratory medicine | 2019 | PMID: 30917047 |
Using Somatic Mutations from Tumors to Classify Variants in Mismatch Repair Genes. | Shirts BH | American journal of human genetics | 2018 | PMID: 29887214 |
Multigene Panel Testing Provides a New Perspective on Lynch Syndrome. | Espenschied CR | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2017 | PMID: 28514183 |
Next-generation sequencing for genetic testing of familial colorectal cancer syndromes. | Simbolo M | Hereditary cancer in clinical practice | 2015 | PMID: 26300997 |
Mutation spectrum and risk of colorectal cancer in African American families with Lynch syndrome. | Guindalini RS | Gastroenterology | 2015 | PMID: 26248088 |
Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database. | Thompson BA | Nature genetics | 2014 | PMID: 24362816 |
Expression defect size among unclassified MLH1 variants determines pathogenicity in Lynch syndrome diagnosis. | Hinrichsen I | Clinical cancer research : an official journal of the American Association for Cancer Research | 2013 | PMID: 23403630 |
Comprehensive functional assessment of MLH1 variants of unknown significance. | Borràs E | Human mutation | 2012 | PMID: 22736432 |
Missense variants in hMLH1 identified in patients from the German HNPCC consortium and functional studies. | Hardt K | Familial cancer | 2011 | PMID: 21404117 |
Integrated analysis of unclassified variants in mismatch repair genes. | Pastrello C | Genetics in medicine : official journal of the American College of Medical Genetics | 2011 | PMID: 21239990 |
Current clinical criteria for Lynch syndrome are not sensitive enough to identify MSH6 mutation carriers. | Sjursen W | Journal of medical genetics | 2010 | PMID: 20587412 |
Comprehensive molecular analysis of mismatch repair gene defects in suspected Lynch syndrome (hereditary nonpolyposis colorectal cancer) cases. | Mueller J | Cancer research | 2009 | PMID: 19690142 |
Functional analysis of human MLH1 variants using yeast and in vitro mismatch repair assays. | Takahashi M | Cancer research | 2007 | PMID: 17510385 |
Interpretation of genetic test results for hereditary nonpolyposis colorectal cancer: implications for clinical predisposition testing. | Syngal S | JAMA | 1999 | PMID: 10422993 |
http://www.insight-database.org/classifications/index.html?gene=MLH1&variant=c.245C%3ET | - | - | - | - |
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Text-mined citations for rs63750005 ...
HelpRecord last updated May 08, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.