ClinVar Genomic variation as it relates to human health
NM_000249.4(MLH1):c.1245T>G (p.Asp415Glu)
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.1245T>G (p.Asp415Glu)
Variation ID: 234772 Accession: VCV000234772.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 37025843 (GRCh38) [ NCBI UCSC ] 3: 37067334 (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 Jan 7, 2017 Sep 29, 2024 Aug 11, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000249.4:c.1245T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000240.1:p.Asp415Glu missense NM_001167617.3:c.951T>G NP_001161089.1:p.Asp317Glu missense NM_001167618.3:c.522T>G NP_001161090.1:p.Asp174Glu missense NM_001167619.3:c.522T>G NP_001161091.1:p.Asp174Glu missense NM_001258271.2:c.1245T>G NP_001245200.1:p.Asp415Glu missense NM_001258273.2:c.522T>G NP_001245202.1:p.Asp174Glu missense NM_001258274.3:c.522T>G NP_001245203.1:p.Asp174Glu missense NM_001354615.2:c.522T>G NP_001341544.1:p.Asp174Glu missense NM_001354616.2:c.522T>G NP_001341545.1:p.Asp174Glu missense NM_001354617.2:c.522T>G NP_001341546.1:p.Asp174Glu missense NM_001354618.2:c.522T>G NP_001341547.1:p.Asp174Glu missense NM_001354619.2:c.522T>G NP_001341548.1:p.Asp174Glu missense NM_001354620.2:c.951T>G NP_001341549.1:p.Asp317Glu missense NM_001354621.2:c.222T>G NP_001341550.1:p.Asp74Glu missense NM_001354622.2:c.222T>G NP_001341551.1:p.Asp74Glu missense NM_001354623.2:c.222T>G NP_001341552.1:p.Asp74Glu missense NM_001354624.2:c.171T>G NP_001341553.1:p.Asp57Glu missense NM_001354625.2:c.171T>G NP_001341554.1:p.Asp57Glu missense NM_001354626.2:c.171T>G NP_001341555.1:p.Asp57Glu missense NM_001354627.2:c.171T>G NP_001341556.1:p.Asp57Glu missense NM_001354628.2:c.1245T>G NP_001341557.1:p.Asp415Glu missense NM_001354629.2:c.1146T>G NP_001341558.1:p.Asp382Glu missense NM_001354630.2:c.1245T>G NP_001341559.1:p.Asp415Glu missense NC_000003.12:g.37025843T>G NC_000003.11:g.37067334T>G NG_007109.2:g.37494T>G LRG_216:g.37494T>G LRG_216t1:c.1245T>G LRG_216p1:p.Asp415Glu - Protein change
- D415E, D174E, D317E, D382E, D57E, D74E
- Other names
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- Canonical SPDI
- NC_000003.12:37025842:T:G
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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.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
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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Uncertain significance (1) |
criteria provided, single submitter
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Aug 11, 2024 | RCV000217953.3 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jun 30, 2023 | RCV000568159.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 6, 2023 | RCV001060734.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 10, 2021 | RCV001328459.1 |
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
(Mar 10, 2021)
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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: SCV001519601.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
Variant summary: MLH1 c.1245T>G (p.Asp415Glu) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign … (more)
Variant summary: MLH1 c.1245T>G (p.Asp415Glu) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251316 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1245T>G has been reported in the literature as a VUS in individuals undergoing multigene panel testing (example, Yorczyk_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance some citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Dec 06, 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: SCV001225441.4
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 415 of the MLH1 … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 415 of the MLH1 protein (p.Asp415Glu). 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: 234772). 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
(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: SCV000684732.4
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces aspartic acid with glutamic acid at codon 415 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this … (more)
This missense variant replaces aspartic acid with glutamic acid at codon 415 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 been identified in at least one individual undergoing hereditary cancer testing (PMID: 25318351). 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
(Jun 30, 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: SCV000669604.6
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
The p.D415E variant (also known as c.1245T>G), located in coding exon 12 of the MLH1 gene, results from a T to G substitution at nucleotide … (more)
The p.D415E variant (also known as c.1245T>G), located in coding exon 12 of the MLH1 gene, results from a T to G substitution at nucleotide position 1245. The aspartic acid at codon 415 is replaced by glutamic acid, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Aug 11, 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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GeneDx
Accession: SCV000279796.10
First in ClinVar: May 29, 2016 Last updated: Sep 29, 2024 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in an individual under going hereditary cancer panel testing (PMID: 25318351); This variant is associated with the following publications: (PMID: 22949387, 22753075, 36243179, 25318351) (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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Use of panel tests in place of single gene tests in the cancer genetics clinic. | Yorczyk A | Clinical genetics | 2015 | PMID: 25318351 |
Text-mined citations for rs750563193 ...
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.