ClinVar Genomic variation as it relates to human health
NM_000249.4(MLH1):c.292G>C (p.Gly98Arg)
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.
Likely pathogenic(3); Uncertain significance(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000249.4(MLH1):c.292G>C (p.Gly98Arg)
Variation ID: 90129 Accession: VCV000090129.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 37001039 (GRCh38) [ NCBI UCSC ] 3: 37042530 (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 Mar 24, 2015 May 1, 2024 Oct 5, 2023 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- G98R, M1I
- Other names
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- Canonical SPDI
- NC_000003.12:37001038:G:C
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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
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
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
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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
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
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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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Sep 28, 2015 | RCV000216356.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Oct 5, 2023 | RCV000693726.4 | |
Likely pathogenic (1) |
criteria provided, single submitter
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May 2, 2023 | RCV001017525.4 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jul 14, 2023 | RCV003451124.1 | |
MLH1-related disorder
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Uncertain significance (1) |
criteria provided, single submitter
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Nov 17, 2022 | RCV003390769.4 |
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
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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Likely pathogenic
(Jul 14, 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: SCV004189397.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
This variant is considered likely pathogenic. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic … (more)
This variant is considered likely pathogenic. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 27363726]. (less)
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Likely pathogenic
(Oct 05, 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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Invitae
Accession: SCV000821607.5
First in ClinVar: Oct 10, 2018 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 98 of the MLH1 protein (p.Gly98Arg). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 98 of the MLH1 protein (p.Gly98Arg). This variant is present in population databases (rs267607725, gnomAD 0.0009%). This missense change has been observed in individual(s) with hereditary non-polyposis colorectal cancer or Lynch syndrome (PMID: 18772310, 21671081). ClinVar contains an entry for this variant (Variation ID: 90129). 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 expected to disrupt MLH1 protein function. This variant disrupts the p.Gly98 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18561205, 22290698). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
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Uncertain significance
(Sep 28, 2015)
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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: SCV000279070.10
First in ClinVar: May 29, 2016 Last updated: Sep 03, 2023 |
Comment:
This variant is denoted MLH1 c.292G>C at the cDNA level, p.Gly98Arg (G98R) at the protein level, and results in the change of a Glycine to … (more)
This variant is denoted MLH1 c.292G>C at the cDNA level, p.Gly98Arg (G98R) at the protein level, and results in the change of a Glycine to an Arginine (GGC>CGC). This variant has been reported in one individual with either colorectal or urothelial cancer and in an individual meeting Amsterdam II criteria whose tumor showed microsatellite instability (MSI-H) but intact expression of the mismatch repair proteins by immunohistochemistry (IHC) (Bujalkova 2008, Kovac 2011). MLH1 Gly98Arg 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 Glycine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Gly98Arg occurs at a position that is conserved across species and is located in the ATPase domain (Hardt 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as one of uncertain significance based on insufficient evidence (Thompson 2014). Based on currently available evidence, we consider MLH1 Gly98Arg to be a variant of uncertain significance. (less)
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Uncertain significance
(Nov 17, 2022)
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criteria provided, single submitter
Method: clinical testing
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MLH1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004120073.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The MLH1 c.292G>C variant is predicted to result in the amino acid substitution p.Gly98Arg. In the primary transcript NM_000249.4, this variant is known as c.292G>C … (more)
The MLH1 c.292G>C variant is predicted to result in the amino acid substitution p.Gly98Arg. In the primary transcript NM_000249.4, this variant is known as c.292G>C (p.Gly98Arg). The p.Gly98Arg variant has been reported in patients with hereditary nonpolyposis colorectal cancer (Patient 20 in Bujalkova et al. 2008. PubMed ID: 18772310; Case 2047/01 in Kovac et al. 2011. PubMed ID: 21671081). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-37042530-G-C) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from uncertain to likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/90129). Of note, another variant impacting this same amino acid (p.Gly98Ser) has been documented; however, clinical or functional evidence was not provided (Ali et al. 2012. PubMed ID: 22290698). Although we suspect that the c.292G>C (p.Gly98Arg) variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Likely pathogenic
(May 02, 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: SCV001178615.6
First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024 |
Comment:
The p.G98R variant (also known as c.292G>C), located in coding exon 3 of the MLH1 gene, results from a G to C substitution at nucleotide … (more)
The p.G98R variant (also known as c.292G>C), located in coding exon 3 of the MLH1 gene, results from a G to C substitution at nucleotide position 292. The glycine at codon 98 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in a patient with non-polyposis colon cancer and a family history that met Amsterdam II criteria. Also, the tumor of this proband displayed high microsatellite instability (MSI-H), but demonstrated normal expression of all four mismatch repair proteins (Kovac MI et al. Fam. Cancer. 2011;10(3):605-16). In another report, this alteration was identified in an individual whose tumor, either colorectal or urothelial, was MSI-H (Bujalkova M et al. Clin. Chem. 2008 Nov;54:1844-54). Based on an internal structural analysis, this alteration blocks the ATP binding site (Ban C et al. Cell. 1999 Apr;97:85-97; Wu H et al. Acta Crystallogr F Struct Biol Commun. 2015 Aug;71:981-5). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (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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Classification of genetic variants in genes associated with Lynch syndrome using a clinical history weighting algorithm. | Morris B | BMC genetics | 2016 | PMID: 27363726 |
Structure of the human MLH1 N-terminus: implications for predisposition to Lynch syndrome. | Wu H | Acta crystallographica. Section F, Structural biology communications | 2015 | PMID: 26249686 |
Classification of mismatch repair gene missense variants with PON-MMR. | Ali H | Human mutation | 2012 | PMID: 22290698 |
Familial colorectal cancer: eleven years of data from a registry program in Switzerland. | Kovac M | Familial cancer | 2011 | PMID: 21671081 |
Multiplex SNaPshot genotyping for detecting loss of heterozygosity in the mismatch-repair genes MLH1 and MSH2 in microsatellite-unstable tumors. | Bujalkova M | Clinical chemistry | 2008 | PMID: 18772310 |
A large fraction of unclassified variants of the mismatch repair genes MLH1 and MSH2 is associated with splicing defects. | Tournier I | Human mutation | 2008 | PMID: 18561205 |
Transformation of MutL by ATP binding and hydrolysis: a switch in DNA mismatch repair. | Ban C | Cell | 1999 | PMID: 10199405 |
Text-mined citations for rs267607725 ...
HelpRecord last updated May 19, 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.