ClinVar Genomic variation as it relates to human health
NM_000249.4(MLH1):c.1327A>C (p.Lys443Gln)
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.
Uncertain significance(4); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000249.4(MLH1):c.1327A>C (p.Lys443Gln)
Variation ID: 89698 Accession: VCV000089698.18
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 3p22.2 3: 37025925 (GRCh38) [ NCBI UCSC ] 3: 37067416 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Oct 19, 2014 May 1, 2024 Nov 14, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000249.4:c.1327A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000240.1:p.Lys443Gln missense NM_001167617.3:c.1033A>C NP_001161089.1:p.Lys345Gln missense NM_001167618.3:c.604A>C NP_001161090.1:p.Lys202Gln missense NM_001167619.3:c.604A>C NP_001161091.1:p.Lys202Gln missense NM_001258271.2:c.1327A>C NP_001245200.1:p.Lys443Gln missense NM_001258273.2:c.604A>C NP_001245202.1:p.Lys202Gln missense NM_001258274.3:c.604A>C NP_001245203.1:p.Lys202Gln missense NM_001354615.2:c.604A>C NP_001341544.1:p.Lys202Gln missense NM_001354616.2:c.604A>C NP_001341545.1:p.Lys202Gln missense NM_001354617.2:c.604A>C NP_001341546.1:p.Lys202Gln missense NM_001354618.2:c.604A>C NP_001341547.1:p.Lys202Gln missense NM_001354619.2:c.604A>C NP_001341548.1:p.Lys202Gln missense NM_001354620.2:c.1033A>C NP_001341549.1:p.Lys345Gln missense NM_001354621.2:c.304A>C NP_001341550.1:p.Lys102Gln missense NM_001354622.2:c.304A>C NP_001341551.1:p.Lys102Gln missense NM_001354623.2:c.304A>C NP_001341552.1:p.Lys102Gln missense NM_001354624.2:c.253A>C NP_001341553.1:p.Lys85Gln missense NM_001354625.2:c.253A>C NP_001341554.1:p.Lys85Gln missense NM_001354626.2:c.253A>C NP_001341555.1:p.Lys85Gln missense NM_001354627.2:c.253A>C NP_001341556.1:p.Lys85Gln missense NM_001354628.2:c.1327A>C NP_001341557.1:p.Lys443Gln missense NM_001354629.2:c.1228A>C NP_001341558.1:p.Lys410Gln missense NM_001354630.2:c.1327A>C NP_001341559.1:p.Lys443Gln missense NC_000003.12:g.37025925A>C NC_000003.11:g.37067416A>C NG_007109.2:g.37576A>C LRG_216:g.37576A>C LRG_216t1:c.1327A>C LRG_216p1:p.Lys443Gln P40692:p.Lys443Gln - Protein change
- K443Q, K202Q, K102Q, K85Q, K345Q, K410Q
- Other names
- -
- Canonical SPDI
- NC_000003.12:37025924:A:C
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
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 | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
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. |
|||
MLH1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
5622 | 5677 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
---|---|---|---|---|
Uncertain significance (1) |
no assertion criteria provided
|
Jul 24, 2014 | RCV000144608.1 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Mar 2, 2023 | RCV000219360.11 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Nov 14, 2023 | RCV000697163.6 | |
Likely benign (1) |
criteria provided, single submitter
|
Apr 1, 2019 | RCV001703974.1 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Aug 8, 2023 | RCV003997108.2 |
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
Help
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
Help
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. |
|
---|---|---|---|---|---|
Likely benign
(Apr 01, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000292610.10
First in ClinVar: Jul 24, 2016 Last updated: Dec 19, 2017 |
Comment:
This variant is associated with the following publications: (PMID: 24933000, 17594722, 22753075, 21120944, 16083711, 21136174, 22949387, 17192056, 20020535, 22045683, 15872200)
|
|
Uncertain significance
(Jan 19, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000274375.8
First in ClinVar: May 29, 2016 Last updated: May 01, 2024 |
Comment:
The p.K443Q variant (also known as c.1327A>C), located in coding exon 12 of the MLH1 gene, results from an A to C substitution at nucleotide … (more)
The p.K443Q variant (also known as c.1327A>C), located in coding exon 12 of the MLH1 gene, results from an A to C substitution at nucleotide position 1327. The lysine at codon 443 is replaced by glutamine, an amino acid with similar properties. This alteration was detected in a patient with a MSI-High colorectal cancer (CRC) that showed loss of MLH1 and PMS2 on IHC, and another patient with CRC that showed loss of MLH1 on IHC (Hampel, H et al. N Engl J Med. 2005 May 5;352(18):1851-60; Drost M, Hum. Mutat. 2010 Mar; 31(3):247-53). However, multiple studies have shown normal MLH1 functional activity (Raevaara TE, Gastroenterology 2005 Aug; 129(2):537-49; Andersen SD, Hum. Mutat. 2012 Dec; 33(12):1647-55; Drost M, Hum. Mutat. 2010 Mar; 31(3):247-53). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. (less)
|
|
Uncertain significance
(Mar 02, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000906441.4
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces lysine with glutamine at codon 443 of the MLH1 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces lysine with glutamine at codon 443 of the MLH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies using recombinant human cells or cell-free assays reported that this variant has mismatch repair activity, localization, and expression comparable to wild type (PMID: 16083711, 20020535). This variant has been reported in individuals affected with Lynch syndrome (PMID: 15872200, 16083711, 22753075) and in an individual affected with gastric cancer (PMID: 15099349). This variant has been identified in 1/31370 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
|
|
Uncertain significance
(Nov 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary nonpolyposis colorectal neoplasms
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000825760.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 443 of the MLH1 protein (p.Lys443Gln). … (more)
This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 443 of the MLH1 protein (p.Lys443Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with colorectal cancer and gastric cancer (PMID: 15099349, 15872200, 16083711). ClinVar contains an entry for this variant (Variation ID: 89698). 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 not expected to disrupt MLH1 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect MLH1 function (PMID: 16083711, 20020535, 21136174, 22753075). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
|
|
Uncertain Significance
(Aug 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004840991.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
|
Comment:
This missense variant replaces lysine with glutamine at codon 443 of the MLH1 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces lysine with glutamine at codon 443 of the MLH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies using recombinant human cells or cell-free assays reported that this variant has mismatch repair activity, localization, and expression comparable to wild type (PMID: 16083711, 20020535). This variant has been reported in individuals affected with Lynch syndrome (PMID: 15872200, 16083711, 22753075) and in an individual affected with gastric cancer (PMID: 15099349). This variant has been identified in 1/31370 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 3
|
|
Uncertain significance
(Jul 24, 2014)
|
no assertion criteria provided
Method: clinical testing
|
Lynch syndrome I
Affected status: unknown
Allele origin:
germline
|
Pathway Genomics
Accession: SCV000189935.1
First in ClinVar: Oct 19, 2014 Last updated: Oct 19, 2014 |
|
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 |
---|---|---|---|---|
Calibration of multiple in silico tools for predicting pathogenicity of mismatch repair gene missense substitutions. | Thompson BA | Human mutation | 2013 | PMID: 22949387 |
Functional characterization of MLH1 missense variants identified in Lynch syndrome patients. | Andersen SD | Human mutation | 2012 | PMID: 22753075 |
Non-truncating hMLH1 variants identified in Slovenian gastric cancer patients are not associated with Lynch Syndrome: a functional analysis report. | Vogelsang M | Familial cancer | 2011 | PMID: 21136174 |
Verification of the three-step model in assessing the pathogenicity of mismatch repair gene variants. | Kansikas M | Human mutation | 2011 | PMID: 21120944 |
A cell-free assay for the functional analysis of variants of the mismatch repair protein MLH1. | Drost M | Human mutation | 2010 | PMID: 20020535 |
Functional analysis helps to clarify the clinical importance of unclassified variants in DNA mismatch repair genes. | Ou J | Human mutation | 2007 | PMID: 17594722 |
Interpreting missense variants: comparing computational methods in human disease genes CDKN2A, MLH1, MSH2, MECP2, and tyrosinase (TYR). | Chan PA | Human mutation | 2007 | PMID: 17370310 |
Functional significance and clinical phenotype of nontruncating mismatch repair variants of MLH1. | Raevaara TE | Gastroenterology | 2005 | PMID: 16083711 |
Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). | Hampel H | The New England journal of medicine | 2005 | PMID: 15872200 |
Mutations in the hMLH1 gene in Slovenian patients with gastric carcinoma. | Hudler P | Clinical genetics | 2004 | PMID: 15099349 |
Text-mined citations for rs34213726 ...
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.