ClinVar Genomic variation as it relates to human health
NM_000249.4(MLH1):c.112A>C (p.Asn38His)
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>C (p.Asn38His)
Variation ID: 89645 Accession: VCV000089645.13
- 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 Mar 24, 2015 Feb 14, 2024 Sep 5, 2013 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- N38H
- Other names
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- Canonical SPDI
- NC_000003.12:36993658:A: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.
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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 |
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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Pathogenic (1) |
reviewed by expert panel
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Sep 5, 2013 | RCV000075115.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 10, 2019 | RCV000129232.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 11, 2019 | RCV001034681.3 | |
not provided (1) |
no classification provided
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- | RCV001804811.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jul 11, 2023 | RCV003451006.1 |
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
(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: SCV000106106.3
First in ClinVar: Dec 19, 2013 Last updated: Dec 24, 2022 |
Comment:
Abrogated function, >2 MSI-H tumours, co-segregation with disease & MAF 0.00. Multifactorial likelihood analysis posterior probability >0.99
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Likely pathogenic
(Jul 11, 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: SCV004187057.1
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: 20020535, 23403630]. This variant has been reported in multiple individuals … (more)
This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 20020535, 23403630]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 20704743]. This variant is expected to disrupt protein structure [Myriad internal data]. (less)
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Pathogenic
(Jan 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: SCV000284006.6
First in ClinVar: Mar 24, 2015 Last updated: Feb 14, 2024 |
Comment:
Experimental studies have shown that this variant reduces the functional activity and expression of the MLH1 protein (PMID: 20020535, 23403630). ¬†Additionally, based on a multifactorial … (more)
Experimental studies have shown that this variant reduces the functional activity and expression of the MLH1 protein (PMID: 20020535, 23403630).  Additionally, based on a multifactorial likelihood algorithm using genetic, functional, and in silico data, this variant has been determined to have a high probability of being pathogenic (PMID: 22949379). This variant was reported in an individual with hereditary non-polyposis colon cancer (HNPCC) (PMID: 12373605) and was reported to segregate with HNPCC in 6 families (PMID: 20704743).  ClinVar contains an entry for this variant (Variation ID: 89645). This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with histidine at codon 38 of the MLH1 protein (p.Asn38His). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and histidine. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 10, 2019)
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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: SCV000183987.7
First in ClinVar: Aug 06, 2014 Last updated: Nov 29, 2022 |
Comment:
The p.N38H pathogenic mutation (also known as c.112A>C), located in coding exon 1 of the MLH1 gene, results from an A to C substitution at … (more)
The p.N38H pathogenic mutation (also known as c.112A>C), located in coding exon 1 of the MLH1 gene, results from an A to C substitution at nucleotide position 112. The asparagine at codon 38 is replaced by histidine, an amino acid with similar properties. In one study, this mutation was detected in six Dutch families with HNPCC/Lynch syndrome, was associated with MSI-H tumors and inconsistent immunohistochemistry (IHC) results, and segregated with disease in all tested affected relatives. Haplotype analysis revealed that all families carried the same ancestral allele, strongly supporting p.N38H as a founder mutation of Dutch origin (van Riel E et al. Hered Cancer Clin Pract 2010; 8:7). The p.N38H mutation has been identified in patients with MSI-H Lynch syndrome-related tumors with isolated loss of PMS2 expression by IHC (van der Klift HM et al. Hum. Mutat. 2016 11;37:1162-1179). Additionally, this mutation demonstrated less than 20% of both relative mismatch repair activity and MLH1 expression in in vitro complementation assays (Drost M et al. Hum. Mutat. 2010 Mar;31:247-53; Hinrichsen I et al. Clin. Cancer Res., 2013 May;19:2432-41) and was predicted to be damaging by a methylation tolerance (MT) functional assay (Bouvet D et al. Gastroenterology, 2019 08;157:421-431). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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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not provided
(-)
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no classification provided
Method: literature only
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Lynch syndrome 1
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV002054081.2
First in ClinVar: Jan 08, 2022 Last updated: Oct 01, 2022 |
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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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Lynch Syndrome. | Adam MP | - | 2021 | PMID: 20301390 |
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 |
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 |
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 multifactorial likelihood model for MMR gene variant classification incorporating probabilities based on sequence bioinformatics and tumor characteristics: a report from the Colon Cancer Family Registry. | Thompson BA | Human mutation | 2013 | PMID: 22949379 |
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 |
http://www.insight-database.org/classifications/index.html?gene=MLH1&variant=c.112A%3EC | - | - | - | - |
Text-mined citations for rs63750580 ...
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.