ClinVar Genomic variation as it relates to human health
NM_000249.4(MLH1):c.2221C>A (p.Leu741Met)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000249.4(MLH1):c.2221C>A (p.Leu741Met)
Variation ID: 187247 Accession: VCV000187247.24
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 37050603 (GRCh38) [ NCBI UCSC ] 3: 37092094 (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 May 29, 2016 Oct 8, 2024 Feb 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000249.4:c.2221C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000240.1:p.Leu741Met missense NM_001167617.3:c.1927C>A NP_001161089.1:p.Leu643Met missense NM_001167618.3:c.1498C>A NP_001161090.1:p.Leu500Met missense NM_001167619.3:c.1498C>A NP_001161091.1:p.Leu500Met missense NM_001258271.2:c.2014C>A NP_001245200.1:p.Leu672Met missense NM_001258273.2:c.1498C>A NP_001245202.1:p.Leu500Met missense NM_001258274.3:c.1498C>A NP_001245203.1:p.Leu500Met missense NM_001354615.2:c.1498C>A NP_001341544.1:p.Leu500Met missense NM_001354616.2:c.1498C>A NP_001341545.1:p.Leu500Met missense NM_001354617.2:c.1498C>A NP_001341546.1:p.Leu500Met missense NM_001354618.2:c.1498C>A NP_001341547.1:p.Leu500Met missense NM_001354619.2:c.1498C>A NP_001341548.1:p.Leu500Met missense NM_001354620.2:c.1927C>A NP_001341549.1:p.Leu643Met missense NM_001354621.2:c.1198C>A NP_001341550.1:p.Leu400Met missense NM_001354622.2:c.1198C>A NP_001341551.1:p.Leu400Met missense NM_001354623.2:c.1198C>A NP_001341552.1:p.Leu400Met missense NM_001354624.2:c.1147C>A NP_001341553.1:p.Leu383Met missense NM_001354625.2:c.1147C>A NP_001341554.1:p.Leu383Met missense NM_001354626.2:c.1147C>A NP_001341555.1:p.Leu383Met missense NM_001354627.2:c.1147C>A NP_001341556.1:p.Leu383Met missense NM_001354628.2:c.2128C>A NP_001341557.1:p.Leu710Met missense NM_001354629.2:c.2122C>A NP_001341558.1:p.Leu708Met missense NM_001354630.2:c.2056C>A NP_001341559.1:p.Leu686Met missense NC_000003.12:g.37050603C>A NC_000003.11:g.37092094C>A NG_007109.2:g.62254C>A LRG_216:g.62254C>A LRG_216t1:c.2221C>A LRG_216p1:p.Leu741Met - Protein change
- L741M, L383M, L672M, L400M, L500M, L710M, L643M, L686M, L708M
- Other names
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- Canonical SPDI
- NC_000003.12:37050602:C:A
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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
Help
The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
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
Help
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 |
5687 | 5747 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
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
Help
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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Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Nov 22, 2023 | RCV000166962.10 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Feb 1, 2024 | RCV000215072.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 5, 2023 | RCV000560309.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 2, 2023 | RCV003995546.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 26, 2023 | RCV004567323.1 |
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
Help
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
Help
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
Help
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
(Nov 22, 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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Ambry Genetics
Accession: SCV000217783.7
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
The p.L741M variant (also known as c.2221C>A), located in coding exon 19 of the MLH1 gene, results from a C to A substitution at nucleotide … (more)
The p.L741M variant (also known as c.2221C>A), located in coding exon 19 of the MLH1 gene, results from a C to A substitution at nucleotide position 2221. The leucine at codon 741 is replaced by methionine, an amino acid with highly similar properties. This variant has been reported in a patient with ovarian cancer at age 46 and a family history of colorectal and other cancers (Ricci MT et al. Tumori, 2019 Aug;105:338-352). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Jun 06, 2022)
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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: SCV000689868.4
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces leucine with methionine at codon 741 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces leucine with methionine at codon 741 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient 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
(Dec 26, 2023)
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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: SCV005058007.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
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Uncertain significance
(Feb 05, 2016)
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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: SCV000279864.9
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
Comment:
This variant is denoted MLH1 c.2221C>A at the cDNA level, p.Leu741Met (L741M) at the protein level, and results in the change of a Leucine to … (more)
This variant is denoted MLH1 c.2221C>A at the cDNA level, p.Leu741Met (L741M) at the protein level, and results in the change of a Leucine to a Methionine (CTG>ATG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Leu741Met was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Leucine and Methionine share similar properties, this is considered a conservative amino acid substitution. MLH1 Leu741Met occurs at a position that is conserved across species and is located within the Pms1p-interactive domain as well as the region of interaction with PMS2, MLH3, and PMS1 (Pang 1997, Raevaara 2005). 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 Leu741Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. (less)
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Uncertain significance
(Dec 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: SCV000625135.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 741 of the MLH1 protein (p.Leu741Met). … (more)
This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 741 of the MLH1 protein (p.Leu741Met). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 187247). 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 not expected to disrupt MLH1 protein function with a negative predictive value of 95%. 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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Uncertain Significance
(Oct 02, 2023)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004843299.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
This missense variant replaces leucine with methionine at codon 741 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces leucine with methionine at codon 741 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Feb 01, 2024)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004704362.7
First in ClinVar: Mar 10, 2024 Last updated: Oct 08, 2024 |
Comment:
MLH1: PM2
Number of individuals with the variant: 1
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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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Development, technical validation, and clinical application of a multigene panel for hereditary gastrointestinal cancer and polyposis. | Ricci MT | Tumori | 2019 | PMID: 31068090 |
Text-mined citations for rs786203583 ...
HelpRecord last updated Oct 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.