ClinVar Genomic variation as it relates to human health
NM_000249.4(MLH1):c.1253A>G (p.Asp418Gly)
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.1253A>G (p.Asp418Gly)
Variation ID: 423761 Accession: VCV000423761.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 37025851 (GRCh38) [ NCBI UCSC ] 3: 37067342 (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 Sep 13, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000249.4:c.1253A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000240.1:p.Asp418Gly missense NM_001167617.3:c.959A>G NP_001161089.1:p.Asp320Gly missense NM_001167618.3:c.530A>G NP_001161090.1:p.Asp177Gly missense NM_001167619.3:c.530A>G NP_001161091.1:p.Asp177Gly missense NM_001258271.2:c.1253A>G NP_001245200.1:p.Asp418Gly missense NM_001258273.2:c.530A>G NP_001245202.1:p.Asp177Gly missense NM_001258274.3:c.530A>G NP_001245203.1:p.Asp177Gly missense NM_001354615.2:c.530A>G NP_001341544.1:p.Asp177Gly missense NM_001354616.2:c.530A>G NP_001341545.1:p.Asp177Gly missense NM_001354617.2:c.530A>G NP_001341546.1:p.Asp177Gly missense NM_001354618.2:c.530A>G NP_001341547.1:p.Asp177Gly missense NM_001354619.2:c.530A>G NP_001341548.1:p.Asp177Gly missense NM_001354620.2:c.959A>G NP_001341549.1:p.Asp320Gly missense NM_001354621.2:c.230A>G NP_001341550.1:p.Asp77Gly missense NM_001354622.2:c.230A>G NP_001341551.1:p.Asp77Gly missense NM_001354623.2:c.230A>G NP_001341552.1:p.Asp77Gly missense NM_001354624.2:c.179A>G NP_001341553.1:p.Asp60Gly missense NM_001354625.2:c.179A>G NP_001341554.1:p.Asp60Gly missense NM_001354626.2:c.179A>G NP_001341555.1:p.Asp60Gly missense NM_001354627.2:c.179A>G NP_001341556.1:p.Asp60Gly missense NM_001354628.2:c.1253A>G NP_001341557.1:p.Asp418Gly missense NM_001354629.2:c.1154A>G NP_001341558.1:p.Asp385Gly missense NM_001354630.2:c.1253A>G NP_001341559.1:p.Asp418Gly missense NC_000003.12:g.37025851A>G NC_000003.11:g.37067342A>G NG_007109.2:g.37502A>G LRG_216:g.37502A>G LRG_216t1:c.1253A>G LRG_216p1:p.Asp418Gly - Protein change
- D418G, D385G, D60G, D320G, D177G, D77G
- Other names
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- Canonical SPDI
- NC_000003.12:37025850:A: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.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 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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Uncertain significance (2) |
criteria provided, single submitter
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Sep 13, 2023 | RCV000482366.5 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jun 14, 2023 | RCV000572056.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 28, 2019 | RCV000987171.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 23, 2023 | RCV001039238.5 |
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
(May 28, 2019)
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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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Mendelics
Accession: SCV001136404.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Uncertain significance
(May 06, 2019)
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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: SCV000689796.3
First in ClinVar: Feb 19, 2018 Last updated: Jun 22, 2020 |
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Uncertain significance
(Sep 13, 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: SCV000573497.5
First in ClinVar: Apr 29, 2017 Last updated: Oct 05, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; In silico … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Observed in at least one individual with a personal history of colon cancer who underwent multi-gene panel testing (Yurgelun et al., 2017); This variant is associated with the following publications: (PMID: 22753075, 27121310, 28135145, 32885271) (less)
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Uncertain significance
(Mar 23, 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: SCV001202758.4
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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: 423761). This missense change has been observed in individual(s) with colorectal cancer (PMID: 28135145). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 418 of the MLH1 protein (p.Asp418Gly). (less)
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Uncertain significance
(Jun 14, 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: SCV000662066.6
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
The p.D418G variant (also known as c.1253A>G), located in coding exon 12 of the MLH1 gene, results from an A to G substitution at nucleotide … (more)
The p.D418G variant (also known as c.1253A>G), located in coding exon 12 of the MLH1 gene, results from an A to G substitution at nucleotide position 1253. The aspartic acid at codon 418 is replaced by glycine, an amino acid with similar properties. This variant has been previously reported in an individual diagnosed with colorectal cancer (Yurgelun MB et al. J Clin Oncol, 2017 Apr;35:1086-1095). This variant was also observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). 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
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001552793.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The MLH1 p.Asp418Gly variant was not identified in the literature nor was it identified in the UMD-LSDB databases. The variant was identified in dbSNP (rs754898711) … (more)
The MLH1 p.Asp418Gly variant was not identified in the literature nor was it identified in the UMD-LSDB databases. The variant was identified in dbSNP (rs754898711) as “with uncertain significance allele” and ClinVar (classified as uncertain significance by Ambry Genetics, GeneDx and Color). The variant was identified in control databases in 1 of 251,348 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 1 of 113,640 chromosomes (freq: 0.000009), while the variant was not observed in the African, Latino, Ashkenazi Jewish, East Asian, Finnish, Other and South Asian populations. The p.Asp418 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict the creation of a new 5’ splice donor site. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (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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Multigene panel testing for hereditary breast and ovarian cancer in the province of Ontario. | Lerner-Ellis J | Journal of cancer research and clinical oncology | 2021 | PMID: 32885271 |
Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer. | Yurgelun MB | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2017 | PMID: 28135145 |
Text-mined citations for rs754898711 ...
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.