ClinVar Genomic variation as it relates to human health
NM_000249.4(MLH1):c.731G>T (p.Gly244Val)
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.
Pathogenic(1); Likely pathogenic(2); 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.731G>T (p.Gly244Val)
Variation ID: 90340 Accession: VCV000090340.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 37014485 (GRCh38) [ NCBI UCSC ] 3: 37055976 (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 31, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000249.4:c.731G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000240.1:p.Gly244Val missense NM_001167617.3:c.437G>T NP_001161089.1:p.Gly146Val missense NM_001167618.3:c.8G>T NP_001161090.1:p.Gly3Val missense NM_001167619.3:c.8G>T NP_001161091.1:p.Gly3Val missense NM_001258271.2:c.731G>T NP_001245200.1:p.Gly244Val missense NM_001258273.2:c.8G>T NP_001245202.1:p.Gly3Val missense NM_001258274.3:c.8G>T NP_001245203.1:p.Gly3Val missense NM_001354615.2:c.8G>T NP_001341544.1:p.Gly3Val missense NM_001354616.2:c.8G>T NP_001341545.1:p.Gly3Val missense NM_001354617.2:c.8G>T NP_001341546.1:p.Gly3Val missense NM_001354618.2:c.8G>T NP_001341547.1:p.Gly3Val missense NM_001354619.2:c.8G>T NP_001341548.1:p.Gly3Val missense NM_001354620.2:c.437G>T NP_001341549.1:p.Gly146Val missense NM_001354621.2:c.-140+2386G>T intron variant NM_001354622.2:c.-199G>T 5 prime UTR NM_001354623.2:c.-199G>T 5 prime UTR NM_001354624.2:c.-96G>T 5 prime UTR NM_001354625.2:c.-96G>T 5 prime UTR NM_001354626.2:c.-96G>T 5 prime UTR NM_001354627.2:c.-96G>T 5 prime UTR NM_001354628.2:c.731G>T NP_001341557.1:p.Gly244Val missense NM_001354629.2:c.632G>T NP_001341558.1:p.Gly211Val missense NM_001354630.2:c.731G>T NP_001341559.1:p.Gly244Val missense NC_000003.12:g.37014485G>T NC_000003.11:g.37055976G>T NG_007109.2:g.26136G>T LRG_216:g.26136G>T LRG_216t1:c.731G>T LRG_216p1:p.Gly244Val P40692:p.Gly244Val - Protein change
- G244V, G146V, G211V, G3V
- Other names
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- Canonical SPDI
- NC_000003.12:37014484:G: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
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The frequency of the allele represented by this VCV record.
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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 |
5624 | 5679 |
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, multiple submitters, no conflicts
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Apr 19, 2019 | RCV000075831.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 4, 2020 | RCV000536939.5 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2023 | RCV002381380.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jul 17, 2023 | RCV003452764.1 |
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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Pathogenic
(Aug 04, 2020)
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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: SCV000625189.5
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. A different missense substitution at this codon (p.Gly244Asp) has been determined to be likely pathogenic … (more)
For these reasons, this variant has been classified as Pathogenic. A different missense substitution at this codon (p.Gly244Asp) has been determined to be likely pathogenic (PMID: 16982745, 17594722). This suggests that the glycine residue is critical for MLH1 protein function and that other missense substitutions at this position may also be pathogenic. Experimental studies have shown that this missense change results in impaired mismatch repair function in vitro (PMID: 17510385, 30998989, 31697235). This variant has been reported in individuals affected with clinical features of Lynch syndrome (PMID: 21642682, 30998989, Invitae). ClinVar contains an entry for this variant (Variation ID: 90340). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with valine at codon 244 of the MLH1 protein (p.Gly244Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. (less)
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Uncertain significance
(May 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome
Affected status: yes
Allele origin:
somatic
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University of Washington Department of Laboratory Medicine, University of Washington
Accession: SCV000887313.1
First in ClinVar: Mar 24, 2015 Last updated: Mar 24, 2015 |
Comment:
MLH1 NM_000249.3:c.731G>T has a 74.5% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 26.5 to 1, generated … (more)
MLH1 NM_000249.3:c.731G>T has a 74.5% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 26.5 to 1, generated from evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at the MLH1 locus. See Shirts et al 2018, PMID 29887214. (less)
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Uncertain significance
(Apr 19, 2019)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome
Affected status: yes
Allele origin:
germline
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Service de Génétique Médicale, Institut Central des Hôpitaux
Accession: SCV000994923.1
First in ClinVar: Oct 03, 2019 Last updated: Oct 03, 2019
Comment:
The missense variant MLH1 c.731G>T is classified as variant of unknown significance (VUS) in the InSight and UMD databases. Takahashi et al report reduced in … (more)
The missense variant MLH1 c.731G>T is classified as variant of unknown significance (VUS) in the InSight and UMD databases. Takahashi et al report reduced in vitro MMR activity for this mutation (PMID: 17510385). MutationTaster and PolyPhen-2 predict that this variant is disease causing and possibly damaging, respectively. gnomAD does not list it, indicating that it is rare. (less)
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Number of individuals with the variant: 1
Comment on evidence:
loss of MLH1 and PMS2 expression
Secondary finding: no
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Likely pathogenic
(Jul 17, 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: SCV004187324.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 30998989, 17510385]. This variant is expected to disrupt protein structure … (more)
This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 30998989, 17510385]. This variant is expected to disrupt protein structure [Myriad internal data]. (less)
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Likely pathogenic
(Oct 31, 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: SCV002668461.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.G244V variant (also known as c.731G>T), located in coding exon 9 of the MLH1 gene, results from a G to T substitution at nucleotide … (more)
The p.G244V variant (also known as c.731G>T), located in coding exon 9 of the MLH1 gene, results from a G to T substitution at nucleotide position 731. The glycine at codon 244 is replaced by valine, an amino acid with dissimilar properties. This alteration has been detected in a family meeting Amsterdam II criteria for Lynch syndrome and the tumor of the proband demonstrated high microsatellite instability, but had normal mismatch repair (MMR) protein expression by immunohistochemistry (Ambry internal data). In one study, protein expression levels in cells expressing this variant were determined to be greater than 75% when compared to the wild type level and MMR activity was reduced compared wild type MLH1 in a complementation assay (Takahashi M et al. Cancer Res. 2007 May;67(10):4595604). This variant also demonstrated deficient activity in a methylation tolerance-based functional assay (Bouvet D et al. Gastroenterology, 2019 08;157:421-431). In another study, steady state levels for this variant were reported to be reduced compared to wild type MLH1 and the p.G244V substitution was predicted to result in destabilization relative to wild type MLH1 (Abildgaard AB et al. Elife, 2019 11;8). The equivalent allele in Bacillus subtilis MutL demonstrated reduced MMR activity and expression, but did not confer a dominant negative effect (Bolz NJ et al. J Bacteriol, 2012 Oct;194:5361-7). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Ambry internal data; 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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Computational and cellular studies reveal structural destabilization and degradation of MLH1 variants in Lynch syndrome. | Abildgaard AB | eLife | 2019 | PMID: 31697235 |
Methylation Tolerance-Based Functional Assay to Assess Variants of Unknown Significance in the MLH1 and MSH2 Genes and Identify Patients With Lynch Syndrome. | Bouvet D | Gastroenterology | 2019 | PMID: 30998989 |
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 |
Residues in the N-terminal domain of MutL required for mismatch repair in Bacillus subtilis. | Bolz NJ | Journal of bacteriology | 2012 | PMID: 22843852 |
Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. | Bonadona V | JAMA | 2011 | PMID: 21642682 |
Functional analysis helps to clarify the clinical importance of unclassified variants in DNA mismatch repair genes. | Ou J | Human mutation | 2007 | PMID: 17594722 |
Functional analysis of human MLH1 variants using yeast and in vitro mismatch repair assays. | Takahashi M | Cancer research | 2007 | PMID: 17510385 |
A human cell-based assay to evaluate the effects of alterations in the MLH1 mismatch repair gene. | Blasi MF | Cancer research | 2006 | PMID: 16982745 |
Text-mined citations for rs63750303 ...
HelpRecord last updated May 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.