ClinVar Genomic variation as it relates to human health
NM_000249.4(MLH1):c.27G>A (p.Arg9=)
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.27G>A (p.Arg9=)
Variation ID: 186982 Accession: VCV000186982.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 36993574 (GRCh38) [ NCBI UCSC ] 3: 37035065 (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 28, 2024 Sep 12, 2023 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- Other names
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- Canonical SPDI
- NC_000003.12:36993573: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
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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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Likely pathogenic (1) |
criteria provided, single submitter
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Sep 28, 2022 | RCV000166655.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Dec 14, 2022 | RCV000471119.8 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Sep 12, 2023 | RCV003468790.1 |
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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Likely pathogenic
(Sep 28, 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: SCV000217460.6
First in ClinVar: Mar 24, 2015 Last updated: Nov 29, 2022 |
Comment:
The c.27G>A variant (also known as p.R9R), located in coding exon 1 of the MLH1 gene, results from a G to A substitution at nucleotide … (more)
The c.27G>A variant (also known as p.R9R), located in coding exon 1 of the MLH1 gene, results from a G to A substitution at nucleotide position 27. This nucleotide substitution does not change the amino acid at codon 9. This alteration was detected along with low-level constitutional MLH1 promoter methylation in a Caucasian male with 3 colorectal cancers, one of which demonstrated high microsatellite instability (MSI-H) with loss of MLH1 protein expression on immunohistochemistry (IHC). The father and mother of this proband were both diagnosed with colorectal cancer as well as a son, who died at age 22 from colorectal cancer. The son also carried the c.27G>A variant allele along with low-level constitutional MLH1 promoter methylation; however, two affected maternal family members did not carry this alteration and were negative for constitutional MLH1 promoter methylation indicating the variant allele may have been paternally inherited (Ward RL et al. Genet. Med. 2013 Jan;15:25-35). This alteration was also reported in a French family that fulfilled Amsterdam I criteria and exhibited low-level constitutional MLH1 promoter methylation. Four family members, two diagnosed with colorectal cancer and two with colorectal adenomas, carried the c.27G>A allele along with low-level constitutional MLH1 promoter methylation. This alteration was identified in another unrelated individual in this study who was diagnosed with colorectal cancer as well as endometrial cancer and had constitutional MLH1 promoter methylation (Leclerc J et al. Genet. Med. 2018 12;20:1589-1599). In our clinical cohort, this alteration also segregated with low-level constitutional MLH1 promoter methylation and disease in families meeting clinical diagnostic criteria for Lynch syndrome (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. RNA studies have demonstrated this alteration does not result in abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Sep 12, 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: SCV004190605.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Likely pathogenic
(Dec 14, 2022)
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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: SCV000555984.8
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
This variant is not present in population databases (gnomAD no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional … (more)
This variant is not present in population databases (gnomAD no frequency). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. ClinVar contains an entry for this variant (Variation ID: 186982). This variant has been observed in individuals with Lynch syndrome-associated tumors and Lynch syndrome (PMID: 22878509, 29790873; Invitae). It has also been observed to segregate with disease in related individuals. This sequence change affects codon 9 of the MLH1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MLH1 protein. (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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Diversity of genetic events associated with MLH1 promoter methylation in Lynch syndrome families with heritable constitutional epimutation. | Leclerc J | Genetics in medicine : official journal of the American College of Medical Genetics | 2018 | PMID: 29790873 |
Identification of constitutional MLH1 epimutations and promoter variants in colorectal cancer patients from the Colon Cancer Family Registry. | Ward RL | Genetics in medicine : official journal of the American College of Medical Genetics | 2013 | PMID: 22878509 |
Text-mined citations for rs759680369 ...
HelpRecord last updated Mar 05, 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.