ClinVar Genomic variation as it relates to human health
NM_000249.4(MLH1):c.1117G>A (p.Gly373Arg)
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.
Uncertain significance(11); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000249.4(MLH1):c.1117G>A (p.Gly373Arg)
Variation ID: 186843 Accession: VCV000186843.23
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 37025715 (GRCh38) [ NCBI UCSC ] 3: 37067206 (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 19, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000249.4:c.1117G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000240.1:p.Gly373Arg missense NM_001167617.3:c.823G>A NP_001161089.1:p.Gly275Arg missense NM_001167618.3:c.394G>A NP_001161090.1:p.Gly132Arg missense NM_001167619.3:c.394G>A NP_001161091.1:p.Gly132Arg missense NM_001258271.2:c.1117G>A NP_001245200.1:p.Gly373Arg missense NM_001258273.2:c.394G>A NP_001245202.1:p.Gly132Arg missense NM_001258274.3:c.394G>A NP_001245203.1:p.Gly132Arg missense NM_001354615.2:c.394G>A NP_001341544.1:p.Gly132Arg missense NM_001354616.2:c.394G>A NP_001341545.1:p.Gly132Arg missense NM_001354617.2:c.394G>A NP_001341546.1:p.Gly132Arg missense NM_001354618.2:c.394G>A NP_001341547.1:p.Gly132Arg missense NM_001354619.2:c.394G>A NP_001341548.1:p.Gly132Arg missense NM_001354620.2:c.823G>A NP_001341549.1:p.Gly275Arg missense NM_001354621.2:c.94G>A NP_001341550.1:p.Gly32Arg missense NM_001354622.2:c.94G>A NP_001341551.1:p.Gly32Arg missense NM_001354623.2:c.94G>A NP_001341552.1:p.Gly32Arg missense NM_001354624.2:c.43G>A NP_001341553.1:p.Gly15Arg missense NM_001354625.2:c.43G>A NP_001341554.1:p.Gly15Arg missense NM_001354626.2:c.43G>A NP_001341555.1:p.Gly15Arg missense NM_001354627.2:c.43G>A NP_001341556.1:p.Gly15Arg missense NM_001354628.2:c.1117G>A NP_001341557.1:p.Gly373Arg missense NM_001354629.2:c.1018G>A NP_001341558.1:p.Gly340Arg missense NM_001354630.2:c.1117G>A NP_001341559.1:p.Gly373Arg missense NC_000003.12:g.37025715G>A NC_000003.11:g.37067206G>A NG_007109.2:g.37366G>A LRG_216:g.37366G>A LRG_216t1:c.1117G>A LRG_216p1:p.Gly373Arg - Protein change
- G373R, G132R, G32R, G340R, G15R, G275R
- Other names
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- Canonical SPDI
- NC_000003.12:37025714:G: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.
Exome Aggregation Consortium (ExAC) 0.00002
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
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 |
5632 | 5687 |
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
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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. |
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Uncertain significance (1) |
criteria provided, single submitter
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Jan 19, 2024 | RCV000226857.8 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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May 5, 2023 | RCV000166495.11 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Jun 21, 2023 | RCV000662540.3 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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May 3, 2021 | RCV000764487.3 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jan 11, 2024 | RCV000708919.4 | |
Likely benign (1) |
criteria provided, single submitter
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Sep 3, 2020 | RCV000484742.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 19, 2021 | RCV001800500.1 |
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
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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
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Muir-Torré syndrome
Mismatch repair cancer syndrome 1 Colorectal cancer, hereditary nonpolyposis, type 2
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000895558.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Uncertain significance
(May 03, 2021)
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criteria provided, single submitter
Method: clinical testing
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Colorectal cancer, hereditary nonpolyposis, type 2
Mismatch repair cancer syndrome 1 Muir-Torré syndrome
Affected status: unknown
Allele origin:
germline
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Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Accession: SCV002495845.1
First in ClinVar: Apr 08, 2022 Last updated: Apr 08, 2022 |
Comment:
MLH1 NM_000249.3 exon 12 p.Gly373Arg (c.1117G>A): This variant has been reported in the literature in one individual with ALL (Zhang 2015 PMID:26580448). This variant is … (more)
MLH1 NM_000249.3 exon 12 p.Gly373Arg (c.1117G>A): This variant has been reported in the literature in one individual with ALL (Zhang 2015 PMID:26580448). This variant is not present in large control databases but is present in ClinVar (Variation ID:186843). Evolutionary conservation and computational predictive tools for this variant are unclear. Splice prediction tools suggest that this variant may affect splicing. However, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. (less)
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Uncertain significance
(May 05, 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: SCV000217294.8
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
The p.G373R variant (also known as c.1117G>A), located in coding exon 12 of the MLH1 gene, results from a G to A substitution at nucleotide … (more)
The p.G373R variant (also known as c.1117G>A), located in coding exon 12 of the MLH1 gene, results from a G to A substitution at nucleotide position 1117. The glycine at codon 373 is replaced by arginine, an amino acid with dissimilar properties. This variant has been reported in 1/1120 pediatric cancer patients who underwent whole-genome sequencing and/or whole-exome sequencing; this patient was diagnosed with hypodiploid acute lymphocytic leukemia (Zhang J et al. N Engl J Med, 2015 Dec;373:2336-2346). This amino acid position is well 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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Likely benign
(Sep 03, 2020)
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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: SCV000569576.4
First in ClinVar: Apr 29, 2017 Last updated: Sep 24, 2021 |
Comment:
Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter … (more)
Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26580448) (less)
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Uncertain significance
(Mar 13, 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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Myriad Genetics, Inc.
Accession: SCV004018124.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
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Uncertain significance
(Jun 21, 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: SCV004192978.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Uncertain significance
(Nov 01, 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: SCV000904056.4
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces glycine with arginine at codon 373 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces glycine with arginine at codon 373 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 reported in an individual affected with leukemia (PMID: 26580448). This variant has been identified in 1/246196 chromosomes 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 11, 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: SCV004840956.1
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 glycine with arginine at codon 373 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more)
This missense variant replaces glycine with arginine at codon 373 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 reported in an individual affected with leukemia (PMID: 26580448). This variant has been identified in 1/246196 chromosomes 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
(Apr 21, 2017)
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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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Counsyl
Accession: SCV000785117.2
First in ClinVar: Jul 15, 2018 Last updated: Jul 15, 2018 |
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Uncertain significance
(Apr 19, 2021)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV002046933.1
First in ClinVar: Jan 03, 2022 Last updated: Jan 03, 2022 |
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Uncertain significance
(Jul 02, 2018)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV000838009.2
First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022 |
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Uncertain significance
(Jan 19, 2024)
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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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Invitae
Accession: SCV000284005.9
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 373 of the MLH1 protein (p.Gly373Arg). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 373 of the MLH1 protein (p.Gly373Arg). This variant is present in population databases (rs766904735, gnomAD no frequency). This missense change has been observed in individual(s) with acute lymphoblastic leukemia (PMID: 26580448). ClinVar contains an entry for this variant (Variation ID: 186843). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MLH1 protein function. 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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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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Germline Mutations in Predisposition Genes in Pediatric Cancer. | Zhang J | The New England journal of medicine | 2015 | PMID: 26580448 |
Text-mined citations for rs766904735 ...
HelpRecord last updated Jun 10, 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.