ClinVar Genomic variation as it relates to human health
NM_000249.4(MLH1):c.778C>T (p.Leu260Phe)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Uncertain significance(5); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000249.4(MLH1):c.778C>T (p.Leu260Phe)
Variation ID: 90349 Accession: VCV000090349.31
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 37014532 (GRCh38) [ NCBI UCSC ] 3: 37056023 (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 Jun 17, 2024 Feb 19, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000249.4:c.778C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000240.1:p.Leu260Phe missense NM_001167617.3:c.484C>T NP_001161089.1:p.Leu162Phe missense NM_001167618.3:c.55C>T NP_001161090.1:p.Leu19Phe missense NM_001167619.3:c.55C>T NP_001161091.1:p.Leu19Phe missense NM_001258271.2:c.778C>T NP_001245200.1:p.Leu260Phe missense NM_001258273.2:c.55C>T NP_001245202.1:p.Leu19Phe missense NM_001258274.3:c.55C>T NP_001245203.1:p.Leu19Phe missense NM_001354615.2:c.55C>T NP_001341544.1:p.Leu19Phe missense NM_001354616.2:c.55C>T NP_001341545.1:p.Leu19Phe missense NM_001354617.2:c.55C>T NP_001341546.1:p.Leu19Phe missense NM_001354618.2:c.55C>T NP_001341547.1:p.Leu19Phe missense NM_001354619.2:c.55C>T NP_001341548.1:p.Leu19Phe missense NM_001354620.2:c.484C>T NP_001341549.1:p.Leu162Phe missense NM_001354621.2:c.-140+2433C>T intron variant NM_001354622.2:c.-152C>T 5 prime UTR NM_001354623.2:c.-152C>T 5 prime UTR NM_001354624.2:c.-49C>T 5 prime UTR NM_001354625.2:c.-49C>T 5 prime UTR NM_001354626.2:c.-49C>T 5 prime UTR NM_001354627.2:c.-49C>T 5 prime UTR NM_001354628.2:c.778C>T NP_001341557.1:p.Leu260Phe missense NM_001354629.2:c.679C>T NP_001341558.1:p.Leu227Phe missense NM_001354630.2:c.778C>T NP_001341559.1:p.Leu260Phe missense NC_000003.12:g.37014532C>T NC_000003.11:g.37056023C>T NG_007109.2:g.26183C>T LRG_216:g.26183C>T LRG_216t1:c.778C>T LRG_216p1:p.Leu260Phe P40692:p.Leu260Phe - Protein change
- L260F, L162F, L227F, L19F
- Other names
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- Canonical SPDI
- NC_000003.12:37014531: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.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
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 |
5689 | 5749 |
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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Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Aug 2, 2023 | RCV000130511.15 | |
Uncertain significance (1) |
criteria provided, single submitter
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Aug 23, 2017 | RCV000479043.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 5, 2023 | RCV000705556.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 19, 2024 | RCV004566932.1 |
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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Uncertain significance
(Feb 19, 2024)
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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: SCV005057978.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
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Uncertain significance
(Aug 23, 2017)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000569663.4
First in ClinVar: Apr 29, 2017 Last updated: Apr 29, 2017 |
Comment:
This variant is denoted MLH1 c.778C>T at the cDNA level, p.Leu260Phe (L260F) at the protein level, and results in the change of a Leucine to … (more)
This variant is denoted MLH1 c.778C>T at the cDNA level, p.Leu260Phe (L260F) at the protein level, and results in the change of a Leucine to a Phenylalanine (CTC>TTC). This variant co-occurred with a pathogenic MSH2 variant in two relatives with early-onset colon cancer belonging to a German family meeting Amsterdam-1 criteria (Hardt 2011). Immunohistochemistry (IHC) on one of the colon tumors demonstrated expression of the MLH1 and PMS2 proteins (Hardt 2011). MSH2 Leu260Phe has also been identified in at least one other individual with a personal and family history suggestive of Lynch syndrome, and an ex vivo splicing assay showed that this variant does not affect splicing (Tournier 2008). However, to our knowledge, the functional impact of the amino acid substitution at the protein level has not been reported. The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as of uncertain significance (Thompson 2014). MLH1 Leu260Phe was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Leucine and Phenylalanine share similar properties, this is considered a conservative amino acid substitution. MLH1 Leu260Phe occurs at a position that is conserved across species and is located in the N-terminal ATPase domain (Andersen 2012). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MLH1 Leu260Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. (less)
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Uncertain significance
(Jan 16, 2022)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002528777.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The MLH1 c.778C>T (p.L260F) variant has been reported in heterozygosity in at least two families fulfilling Amsterdam II criteria (PMID: 18561205, 21404117). However, one of … (more)
The MLH1 c.778C>T (p.L260F) variant has been reported in heterozygosity in at least two families fulfilling Amsterdam II criteria (PMID: 18561205, 21404117). However, one of these families was also noted to have an MSH2 pathogenic variant that segregated with disease in at least one individual and showed retained MLH1 protein expression on immunohistochemistry (PMID: 21404117). It has also been seen in individuals with breast cancer (PMID: 12173039, 33471991). Functional studies have shown that this variant causes a partial reduction in MMR function in a methylation-tolerance assay (PMID: 30998989). The variant was not shown to impact splicing in patient lymphocytes or a splicing minigene assay (PMID: 18561205). It was observed in 1/250762 chromosomes across all populations in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). The variant has been reported in ClinVar (Variation ID 90349). In silico tools suggest the impact of the variant on protein function is deleterious. The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)
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Uncertain significance
(Aug 02, 2023)
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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: SCV000684864.5
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces leucine with phenylalanine at codon 260 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces leucine with phenylalanine at codon 260 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). A functional study has shown that this variant causes a partial loss of mismatch repair (MMR) function in methylation tolerance-based functional assay (PMID: 30998989), strong loss of MMR function when expressed in insect cells (PMID: 27629256), and does not impact RNA splicing in minigene assay and in RT-PCR using cells from an individual who carries this variant (PMID: 18561205). This variant has been reported in three families affected with Lynch syndrome (PMID: 18561205, 21404117, 27629256) and in an individual affected with breast cancer (PMID: 12173039). In one of the Lynch syndrome families who harbored this variant, two family members affected with colon cancer were determined to carry another pathogenic variant in the MSH2 gene, which could explain the observed phenotype (PMID: 21404117). This variant has been identified in 1/250762 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, additional clinical and functional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Oct 05, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000834557.5
First in ClinVar: Oct 10, 2018 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 260 of the MLH1 protein (p.Leu260Phe). … (more)
This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 260 of the MLH1 protein (p.Leu260Phe). This variant is present in population databases (rs63750642, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 30998989; 21404117)). ClinVar contains an entry for this variant (Variation ID: 90349). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MLH1 protein function. Experimental studies have shown that this missense change affects MLH1 function (PMID: 30998989). This variant disrupts the p.Leu260 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22290698, 24362816, 27629256). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Likely benign
(Oct 09, 2017)
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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: SCV000185380.8
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (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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Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
Methylation Tolerance-Based Functional Assay to Assess Variants of Unknown Significance in the MLH1 and MSH2 Genes and Identify Patients With Lynch Syndrome. | Bouvet D | Gastroenterology | 2019 | PMID: 30998989 |
Assessment of the InSiGHT Interpretation Criteria for the Clinical Classification of 24 MLH1 and MSH2 Gene Variants. | Tricarico R | Human mutation | 2017 | PMID: 27629256 |
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 |
Classification of mismatch repair gene missense variants with PON-MMR. | Ali H | Human mutation | 2012 | PMID: 22290698 |
Missense variants in hMLH1 identified in patients from the German HNPCC consortium and functional studies. | Hardt K | Familial cancer | 2011 | PMID: 21404117 |
A large fraction of unclassified variants of the mismatch repair genes MLH1 and MSH2 is associated with splicing defects. | Tournier I | Human mutation | 2008 | PMID: 18561205 |
Genetic and epigenetic modification of mismatch repair genes hMSH2 and hMLH1 in sporadic breast cancer with microsatellite instability. | Murata H | Oncogene | 2002 | PMID: 12173039 |
Text-mined citations for rs63750642 ...
HelpRecord last updated Sep 29, 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.