ClinVar Genomic variation as it relates to human health
NM_000249.4(MLH1):c.86C>G (p.Ala29Gly)
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.86C>G (p.Ala29Gly)
Variation ID: 90403 Accession: VCV000090403.8
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 36993633 (GRCh38) [ NCBI UCSC ] 3: 37035124 (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 Feb 14, 2024 Sep 5, 2013 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- A29G
- Other names
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- Canonical SPDI
- NC_000003.12:36993632:C: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.
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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 |
5529 | 5584 |
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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Pathogenic (1) |
reviewed by expert panel
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Sep 5, 2013 | RCV000075896.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 29, 2022 | RCV000218998.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Aug 13, 2020 | RCV001284650.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jul 10, 2023 | RCV003452780.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 13, 2023 | RCV003593891.1 |
Submissions - Germline
Classification
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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
(Sep 05, 2013)
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reviewed by expert panel
Method: research
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Lynch Syndrome
Affected status: unknown
Allele origin:
germline
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International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
Accession: SCV000106912.3
First in ClinVar: Dec 19, 2013 Last updated: Dec 24, 2022 |
Comment:
Variant causes splicing aberrations: full inactivation of variant allele. In-frame transcript interrupts ATPase domain.
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Likely pathogenic
(Aug 13, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001470543.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
Comment:
Not found in the total gnomAD dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. … (more)
Not found in the total gnomAD dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function. (less)
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Likely pathogenic
(Jul 10, 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: SCV004185816.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 10734316].
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Pathogenic
(Oct 13, 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: SCV004293445.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 29 of the MLH1 protein (p.Ala29Gly). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 29 of the MLH1 protein (p.Ala29Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Lynch syndrome (PMID: 10734316, 21642682, 28514183, 34178123; Invitae). ClinVar contains an entry for this variant (Variation ID: 90403). 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. Studies have shown that this missense change is associated with altered splicing resulting in unknown protein product impact (Invitae). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Sep 29, 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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Ambry Genetics
Accession: SCV000276711.6
First in ClinVar: May 29, 2016 Last updated: Nov 29, 2022 |
Comment:
The p.A29G pathogenic mutation (also known as c.86C>G), located in coding exon 1 of the MLH1 gene, results from a C to G substitution at … (more)
The p.A29G pathogenic mutation (also known as c.86C>G), located in coding exon 1 of the MLH1 gene, results from a C to G substitution at nucleotide position 86. The alanine at codon 29 is replaced by glycine, an amino acid with similar properties.This pathogenic muation was reported in a Japanese family with Turcot syndrome where the 16 year old proband had been diagnosed with a glioblastoma. Authors showed that this mutation created a new cryptic splice donor site resulting in two transcripts of the MLH1 protein which were equally represented. One of the transcripts contained a frameshift leading to a premature stop codon, and the second transcript contained an in-frame deletion of 12 codons (Kanamori M et al. Oncogene. 2000 Mar 16;19(12):1564-71). This alteration has been classified as pathogenic using the following lines of evidence: in silico prediction models, segregation with disease, clinical phenotype including tumor characteristics, mutation co-occurrence, and functional studies (Thompson BA et al. Hum. Mutat. 2013 Jan;34:200-9; Thompson BA et al. Nat. Genet. 2014 Feb;46:107-15; available at [www.insight-group.org/variants/classifications/]). This amino acid position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration creates a new and highly competitive cryptic donor splice site. In addition, this alteration is predicted to be deleterious by in silico analysis. In addition, this alteration is predicted to be borderline deleterious by MAPP-MMR in silico analyses (Chao EC et al. Hum. Mutat. 2008 Jun;29:852-60). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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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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Development and external validation of a novel nomogram for screening Chinese Lynch syndrome: based on a multicenter, population study. | Yang M | Therapeutic advances in medical oncology | 2021 | PMID: 34178123 |
Multigene Panel Testing Provides a New Perspective on Lynch Syndrome. | Espenschied CR | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2017 | PMID: 28514183 |
Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database. | Thompson BA | Nature genetics | 2014 | PMID: 24362816 |
Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. | Bonadona V | JAMA | 2011 | PMID: 21642682 |
Microsatellite instability and the PTEN1 gene mutation in a subset of early onset gliomas carrying germline mutation or promoter methylation of the hMLH1 gene. | Kanamori M | Oncogene | 2000 | PMID: 10734316 |
http://www.insight-database.org/classifications/index.html?gene=MLH1&variant=c.86C%3EG | - | - | - | - |
Text-mined citations for rs63750216 ...
HelpRecord last updated Feb 20, 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.