This variant is denoted MLH1 c.2093C>T at the cDNA level, p.Ser698Leu (S698L) at the protein level, and results in the change of a Serine to a Leucine (TCA>TTA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Ser698Leu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Serine and Leucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Ser698Leu occurs at a position that is highly conserved across mammals and is located in the region that interacts with PMS2/MLH3/PMS1 (Raevaara 2005). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MLH1 Ser698Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
ClinVar Genomic variation as it relates to human health
NM_000249.4(MLH1):c.2093C>T (p.Ser698Leu)
Germline
Classification
Help
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.
(5)
Help
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
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000249.4(MLH1):c.2093C>T (p.Ser698Leu)
Variation ID: 418307 Accession: VCV000418307.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 37049007 (GRCh38) [ NCBI UCSC ] 3: 37090498 (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 Apr 29, 2017 May 1, 2024 Jan 24, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000249.4:c.2093C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000240.1:p.Ser698Leu missense NM_001167617.3:c.1799C>T NP_001161089.1:p.Ser600Leu missense NM_001167618.3:c.1370C>T NP_001161090.1:p.Ser457Leu missense NM_001167619.3:c.1370C>T NP_001161091.1:p.Ser457Leu missense NM_001258271.2:c.1896+1324C>T intron variant NM_001258273.2:c.1370C>T NP_001245202.1:p.Ser457Leu missense NM_001258274.3:c.1370C>T NP_001245203.1:p.Ser457Leu missense NM_001354615.2:c.1370C>T NP_001341544.1:p.Ser457Leu missense NM_001354616.2:c.1370C>T NP_001341545.1:p.Ser457Leu missense NM_001354617.2:c.1370C>T NP_001341546.1:p.Ser457Leu missense NM_001354618.2:c.1370C>T NP_001341547.1:p.Ser457Leu missense NM_001354619.2:c.1370C>T NP_001341548.1:p.Ser457Leu missense NM_001354620.2:c.1799C>T NP_001341549.1:p.Ser600Leu missense NM_001354621.2:c.1070C>T NP_001341550.1:p.Ser357Leu missense NM_001354622.2:c.1070C>T NP_001341551.1:p.Ser357Leu missense NM_001354623.2:c.1070C>T NP_001341552.1:p.Ser357Leu missense NM_001354624.2:c.1019C>T NP_001341553.1:p.Ser340Leu missense NM_001354625.2:c.1019C>T NP_001341554.1:p.Ser340Leu missense NM_001354626.2:c.1019C>T NP_001341555.1:p.Ser340Leu missense NM_001354627.2:c.1019C>T NP_001341556.1:p.Ser340Leu missense NM_001354628.2:c.2000C>T NP_001341557.1:p.Ser667Leu missense NM_001354629.2:c.1994C>T NP_001341558.1:p.Ser665Leu missense NM_001354630.2:c.1928C>T NP_001341559.1:p.Ser643Leu missense NC_000003.12:g.37049007C>T NC_000003.11:g.37090498C>T NG_007109.2:g.60658C>T LRG_216:g.60658C>T LRG_216t1:c.2093C>T LRG_216p1:p.Ser698Leu - Protein change
- S698L, S643L, S357L, S457L, S665L, S600L, S667L, S340L
- Other names
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- Canonical SPDI
- NC_000003.12:37049006: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
Help
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
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. |
|||
| MLH1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
5691 | 5752 | |
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
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Uncertain significance (1) |
criteria provided, single submitter
|
Jan 2, 2015 | RCV000478844.1 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 24, 2024 | RCV001014407.6 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Jan 17, 2023 | RCV002525766.3 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Jan 11, 2024 | RCV004002244.2 |
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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|---|---|---|---|---|---|
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Uncertain significance
(Jan 02, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000565169.3
First in ClinVar: Apr 29, 2017 Last updated: Apr 29, 2017 |
Comment:
This variant is denoted MLH1 c.2093C>T at the cDNA level, p.Ser698Leu (S698L) at the protein level, and results in the change of a Serine to … (more)
This variant is denoted MLH1 c.2093C>T at the cDNA level, p.Ser698Leu (S698L) at the protein level, and results in the change of a Serine to a Leucine (TCA>TTA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Ser698Leu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Serine and Leucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Ser698Leu occurs at a position that is highly conserved across mammals and is located in the region that interacts with PMS2/MLH3/PMS1 (Raevaara 2005). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MLH1 Ser698Leu is pathogenic or benign. We consider it to be a variant of uncertain significance. (less)
|
|
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Uncertain significance
(Jan 02, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV001347596.2
First in ClinVar: Jun 22, 2020 Last updated: Jan 12, 2022 |
Comment:
This missense variant replaces serine with leucine at codon 698 of the MLH1 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces serine with leucine at codon 698 of the MLH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed 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
(Jan 24, 2024)
|
criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV001175107.4
First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024 |
Comment:
The p.S698L variant (also known as c.2093C>T), located in coding exon 18 of the MLH1 gene, results from a C to T substitution at nucleotide … (more)
The p.S698L variant (also known as c.2093C>T), located in coding exon 18 of the MLH1 gene, results from a C to T substitution at nucleotide position 2093. The serine at codon 698 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear. (less)
|
|
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Uncertain significance
(Jan 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
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Hereditary nonpolyposis colorectal neoplasms
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002982983.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 28, 2024 |
Comment:
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 … (more)
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. 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. ClinVar contains an entry for this variant (Variation ID: 418307). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 698 of the MLH1 protein (p.Ser698Leu). (less)
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|
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Uncertain Significance
(Jan 11, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004843277.1
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)
|
Comment:
This missense variant replaces serine with leucine at codon 698 of the MLH1 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces serine with leucine at codon 698 of the MLH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed 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
|
Comment:
Comment:
This missense variant replaces serine with leucine at codon 698 of the MLH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed 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.
Comment:
The p.S698L variant (also known as c.2093C>T), located in coding exon 18 of the MLH1 gene, results from a C to T substitution at nucleotide position 2093. The serine at codon 698 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear.
Comment:
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. 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. ClinVar contains an entry for this variant (Variation ID: 418307). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 698 of the MLH1 protein (p.Ser698Leu).
Comment:
This missense variant replaces serine with leucine at codon 698 of the MLH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed 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.
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. |
Comment:
This variant is denoted MLH1 c.2093C>T at the cDNA level, p.Ser698Leu (S698L) at the protein level, and results in the change of a Serine to a Leucine (TCA>TTA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Ser698Leu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Serine and Leucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Ser698Leu occurs at a position that is highly conserved across mammals and is located in the region that interacts with PMS2/MLH3/PMS1 (Raevaara 2005). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MLH1 Ser698Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Comment:
This missense variant replaces serine with leucine at codon 698 of the MLH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed 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.
Comment:
The p.S698L variant (also known as c.2093C>T), located in coding exon 18 of the MLH1 gene, results from a C to T substitution at nucleotide position 2093. The serine at codon 698 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear.
Comment:
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. 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. ClinVar contains an entry for this variant (Variation ID: 418307). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 698 of the MLH1 protein (p.Ser698Leu).
Comment:
This missense variant replaces serine with leucine at codon 698 of the MLH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed 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.
Citations for germline classification of this variant
Help| There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar. |
Text-mined citations for rs587778975 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record 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.