ClinVar Genomic variation as it relates to human health
NM_000249.4(MLH1):c.2080_2081inv (p.Glu694Ser)
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.2080_2081inv (p.Glu694Ser)
Variation ID: 455415 Accession: VCV000455415.22
- Type and length
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Inversion, 2 bp
- Location
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Cytogenetic: 3p22.2 3: 37048994-37048995 (GRCh38) [ NCBI UCSC ] 3: 37090485-37090486 (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 Feb 19, 2018 Jun 17, 2024 Feb 5, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000249.4:c.2080_2081delinsTC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000249.4:c.2080_2081inv MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000240.1:p.Glu694Ser missense NM_001167617.3:c.1786_1787inv NP_001161089.1:p.Glu596Ser missense NM_001167618.3:c.1357_1358inv NP_001161090.1:p.Glu453Ser missense NM_001167619.3:c.1357_1358inv NP_001161091.1:p.Glu453Ser missense NM_001258271.2:c.1896+1311_1896+1312inv intron variant NM_001258273.2:c.1357_1358inv NP_001245202.1:p.Glu453Ser missense NM_001258274.3:c.1357_1358inv NP_001245203.1:p.Glu453Ser missense NM_001354615.2:c.1357_1358inv NP_001341544.1:p.Glu453Ser missense NM_001354616.2:c.1357_1358inv NP_001341545.1:p.Glu453Ser missense NM_001354617.2:c.1357_1358inv NP_001341546.1:p.Glu453Ser missense NM_001354618.2:c.1357_1358inv NP_001341547.1:p.Glu453Ser missense NM_001354619.2:c.1357_1358inv NP_001341548.1:p.Glu453Ser missense NM_001354620.2:c.1786_1787inv NP_001341549.1:p.Glu596Ser missense NM_001354621.2:c.1057_1058inv NP_001341550.1:p.Glu353Ser missense NM_001354622.2:c.1057_1058inv NP_001341551.1:p.Glu353Ser missense NM_001354623.2:c.1057_1058inv NP_001341552.1:p.Glu353Ser missense NM_001354624.2:c.1006_1007inv NP_001341553.1:p.Glu336Ser missense NM_001354625.2:c.1006_1007inv NP_001341554.1:p.Glu336Ser missense NM_001354626.2:c.1006_1007inv NP_001341555.1:p.Glu336Ser missense NM_001354627.2:c.1006_1007inv NP_001341556.1:p.Glu336Ser missense NM_001354628.2:c.1987_1988inv NP_001341557.1:p.Glu663Ser missense NM_001354629.2:c.1981_1982inv NP_001341558.1:p.Glu661Ser missense NM_001354630.2:c.1915_1916inv NP_001341559.1:p.Glu639Ser missense NC_000003.12:g.37048994_37048995inv NC_000003.11:g.37090485_37090486inv NG_007109.2:g.60645_60646inv LRG_216:g.60645_60646inv - Protein change
- E353S, E661S, E663S, E336S, E639S, E453S, E596S, E694S
- Other names
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- Canonical SPDI
- NC_000003.12:37048993:GA:TC
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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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- Links
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
Help
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
Help
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 |
5683 | 5744 |
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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Oct 11, 2023 | RCV000219102.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 5, 2022 | RCV000556535.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 28, 2023 | RCV000589333.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 16, 2023 | RCV000855650.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 5, 2024 | RCV003459173.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 8, 2024 | RCV004003719.2 |
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
(Oct 05, 2022)
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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: SCV000625123.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with serine, which is neutral and polar, at codon 694 of the MLH1 protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with serine, which is neutral and polar, at codon 694 of the MLH1 protein (p.Glu694Ser). This variant is present in population databases (no rsID available, gnomAD 0.2%). This missense change has been observed in individual(s) with sarcoma (PMID: 25712765). ClinVar contains an entry for this variant (Variation ID: 455415). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). 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
(Jan 28, 2023)
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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: SCV000569500.6
First in ClinVar: Apr 29, 2017 Last updated: May 20, 2023 |
Comment:
Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this variant does not alter protein structure/function; Observed in … (more)
Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this variant does not alter protein structure/function; Observed in an individual with sarcoma who also carried a pathogenic variant in BRCA2 (Varga et al., 2015); This variant is associated with the following publications: (PMID: 23695190, 25712765, 12799449, 20533529, 22753075) (less)
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Uncertain significance
(Oct 16, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000696143.3
First in ClinVar: Mar 17, 2018 Last updated: Nov 20, 2023 |
Comment:
Variant summary: MLH1 c.2080_2081delinsTC (p.Glu694Ser) results in a non-conservative amino acid change located in the C-terminal domain (IPR032189) of the encoded protein sequence. Three of … (more)
Variant summary: MLH1 c.2080_2081delinsTC (p.Glu694Ser) results in a non-conservative amino acid change located in the C-terminal domain (IPR032189) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. This variant is reported as two separate single nucleotide changes in gnomAD, with both variants found in the same subpopulations with the same number of occurrences, and read data demonstrating that both of these SNPs occurred together in cis, in 3 cases. Therefore the variant allele was found at a frequency of 2e-05 in 251054 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2080_2081delinsTC has been reported in the literature in an individual affected with sarcoma, who also carried a BRCA2 pathogenic allele (Varga_2015). This report does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 25712765). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Apr 25, 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: SCV000684797.5
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This variant causes a deletion of GA and insertion of TC at nucleotide positions 2080 and 2081 in exon 18 of the MLH1 gene, which … (more)
This variant causes a deletion of GA and insertion of TC at nucleotide positions 2080 and 2081 in exon 18 of the MLH1 gene, which replaces glutamic acid with serine at codon 694 of the MLH1 protein. This substitution changes two basepairs, c.2080G>T and c.2081A>C, which together changes the codon for glutamic acid (GAG) to one for serine (TCG). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with early onset, microsatellite unstable colorectal cancer (PMID: 33753878), as well as in an individual affected with sarcoma who also carried a pathogenic variant in the BRCA2 gene (PMID: 25712765). 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
(Jan 08, 2024)
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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: SCV004843271.1
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 variant causes a deletion of GA and insertion of TC at nucleotide positions 2080 and 2081 in exon 18 of the MLH1 gene, which … (more)
This variant causes a deletion of GA and insertion of TC at nucleotide positions 2080 and 2081 in exon 18 of the MLH1 gene, which replaces glutamic acid with serine at codon 694 of the MLH1 protein. This substitution changes two basepairs, c.2080G>T and c.2081A>C, which together changes the codon for glutamic acid (GAG) to one for serine (TCG). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with early onset, microsatellite unstable colorectal cancer (PMID: 33753878), as well as in an individual affected with sarcoma who also carried a pathogenic variant in the BRCA2 gene (PMID: 25712765). 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: 4
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Uncertain significance
(Oct 11, 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: SCV000274942.7
First in ClinVar: May 29, 2016 Last updated: May 01, 2024 |
Comment:
The c.2080_2081delGAinsTC variant (also known as p.E694S), located in coding exon 18 of the MLH1 gene, results from an in-frame deletion of GA and insertion … (more)
The c.2080_2081delGAinsTC variant (also known as p.E694S), located in coding exon 18 of the MLH1 gene, results from an in-frame deletion of GA and insertion of TC at nucleotide positions 2080 to 2081. This results in the substitution of the glutamic acid residue for a serine residue at codon 694, an amino acid with similar properties. This alteration has been identified in a patient whose colon tumor demonstrated microsatellite instability, absent MLH1 staining by IHC, and loss of heterozygosity (Kim JE et al. Exp Mol Med, 2021 Mar;53:446-456). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Feb 05, 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: SCV004192980.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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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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High prevalence of TP53 loss and whole-genome doubling in early-onset colorectal cancer. | Kim JE | Experimental & molecular medicine | 2021 | PMID: 33753878 |
The importance of proper bioinformatics analysis and clinical interpretation of tumor genomic profiling: a case study of undifferentiated sarcoma and a constitutional pathogenic BRCA2 mutation and an MLH1 variant of uncertain significance. | Varga E | Familial cancer | 2015 | PMID: 25712765 |
Text-mined citations for this variant ...
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.