ClinVar Genomic variation as it relates to human health
NM_000249.4(MLH1):c.112A>T (p.Asn38Tyr)
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.112A>T (p.Asn38Tyr)
Variation ID: 955911 Accession: VCV000955911.10
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 36993659 (GRCh38) [ NCBI UCSC ] 3: 37035150 (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 Jul 16, 2020 Feb 20, 2024 Dec 3, 2021 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- N38Y
- Other names
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- Canonical SPDI
- NC_000003.12:36993658:A: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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- Links
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 |
5564 | 5619 |
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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Likely pathogenic (1) |
criteria provided, single submitter
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Aug 11, 2019 | RCV001228630.4 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Feb 12, 2021 | RCV001507618.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 3, 2021 | RCV002322102.1 |
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
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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
(Feb 12, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001713272.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Comment:
PM2, PM5, PP3, PP4
Number of individuals with the variant: 1
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Pathogenic
(Dec 03, 2021)
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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: SCV002607770.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.N38Y pathogenic mutation (also known as c.112A>T), located in coding exon 1 of the MLH1 gene, results from an A to T substitution at … (more)
The p.N38Y pathogenic mutation (also known as c.112A>T), located in coding exon 1 of the MLH1 gene, results from an A to T substitution at nucleotide position 112. The asparagine at codon 38 is replaced by tyrosine, an amino acid with dissimilar properties. This variant has been identified in a proband(s) whose Lynch syndrome-associated tumor demonstrated high microsatellite instability and loss of MLH1/PMS2 expression by immunohistochemistry (Ambry internal data). Based on internal structural analysis, N38Y abrogates a critical ion-binding site in the MLH1 ATPase domain (Wu H et al. Acta Crystallogr F Struct Biol Commun, 2015 Aug;71:981-5; Ambry internal data). Another alteration at the same codon, p.N38H (c.112A>C), segregates in affected members of families who meet Amsterdam criteria (van Riel E et al. Hered Cancer Clin Pract, 2010 Aug;8:7). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Aug 11, 2019)
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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: SCV001401038.4
First in ClinVar: Jul 16, 2020 Last updated: Feb 20, 2024 |
Comment:
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 … (more)
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. This variant disrupts the p.Asn38 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12373605, 20704743, 27435373, 28514183, 20020535, 23403630). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed to segregate with clinical features of Lynch syndrome in a family (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with tyrosine at codon 38 of the MLH1 protein (p.Asn38Tyr). The asparagine residue is highly conserved and there is a large physicochemical difference between asparagine and tyrosine. (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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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 |
Comprehensive Mutation Analysis of PMS2 in a Large Cohort of Probands Suspected of Lynch Syndrome or Constitutional Mismatch Repair Deficiency Syndrome. | van der Klift HM | Human mutation | 2016 | PMID: 27435373 |
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 |
Expression defect size among unclassified MLH1 variants determines pathogenicity in Lynch syndrome diagnosis. | Hinrichsen I | Clinical cancer research : an official journal of the American Association for Cancer Research | 2013 | PMID: 23403630 |
A novel pathogenic MLH1 missense mutation, c.112A > C, p.Asn38His, in six families with Lynch syndrome. | van Riel E | Hereditary cancer in clinical practice | 2010 | PMID: 20704743 |
A cell-free assay for the functional analysis of variants of the mismatch repair protein MLH1. | Drost M | Human mutation | 2010 | PMID: 20020535 |
Genomic deletions of MSH2 and MLH1 in colorectal cancer families detected by a novel mutation detection approach. | Gille JJ | British journal of cancer | 2002 | PMID: 12373605 |
Text-mined citations for rs63750580 ...
HelpRecord last updated Feb 28, 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.