ClinVar Genomic variation as it relates to human health
NM_000249.4(MLH1):c.1693A>T (p.Ile565Phe)
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.1693A>T (p.Ile565Phe)
Variation ID: 89842 Accession: VCV000089842.46
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 37042293 (GRCh38) [ NCBI UCSC ] 3: 37083784 (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 Aug 4, 2024 Jan 11, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000249.4:c.1693A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000240.1:p.Ile565Phe missense NM_001167617.3:c.1399A>T NP_001161089.1:p.Ile467Phe missense NM_001167618.3:c.970A>T NP_001161090.1:p.Ile324Phe missense NM_001167619.3:c.970A>T NP_001161091.1:p.Ile324Phe missense NM_001258271.2:c.1693A>T NP_001245200.1:p.Ile565Phe missense NM_001258273.2:c.970A>T NP_001245202.1:p.Ile324Phe missense NM_001258274.3:c.970A>T NP_001245203.1:p.Ile324Phe missense NM_001354615.2:c.970A>T NP_001341544.1:p.Ile324Phe missense NM_001354616.2:c.970A>T NP_001341545.1:p.Ile324Phe missense NM_001354617.2:c.970A>T NP_001341546.1:p.Ile324Phe missense NM_001354618.2:c.970A>T NP_001341547.1:p.Ile324Phe missense NM_001354619.2:c.970A>T NP_001341548.1:p.Ile324Phe missense NM_001354620.2:c.1399A>T NP_001341549.1:p.Ile467Phe missense NM_001354621.2:c.670A>T NP_001341550.1:p.Ile224Phe missense NM_001354622.2:c.670A>T NP_001341551.1:p.Ile224Phe missense NM_001354623.2:c.670A>T NP_001341552.1:p.Ile224Phe missense NM_001354624.2:c.619A>T NP_001341553.1:p.Ile207Phe missense NM_001354625.2:c.619A>T NP_001341554.1:p.Ile207Phe missense NM_001354626.2:c.619A>T NP_001341555.1:p.Ile207Phe missense NM_001354627.2:c.619A>T NP_001341556.1:p.Ile207Phe missense NM_001354628.2:c.1693A>T NP_001341557.1:p.Ile565Phe missense NM_001354629.2:c.1594A>T NP_001341558.1:p.Ile532Phe missense NM_001354630.2:c.1693A>T NP_001341559.1:p.Ile565Phe missense NC_000003.12:g.37042293A>T NC_000003.11:g.37083784A>T NG_007109.2:g.53944A>T LRG_216:g.53944A>T LRG_216t1:c.1693A>T LRG_216p1:p.Ile565Phe P40692:p.Ile565Phe - Protein change
- I565F, I467F, I207F, I224F, I324F, I532F
- Other names
- p.I565F:ATT>TTT
- Canonical SPDI
- NC_000003.12:37042292: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
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 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 | ||
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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 |
5683 | 5744 |
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
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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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Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Nov 16, 2023 | RCV000234862.11 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jul 22, 2022 | RCV000160538.25 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 3, 2024 | RCV000627705.8 | |
Uncertain significance (2) |
criteria provided, single submitter
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Jan 11, 2024 | RCV001354474.5 |
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
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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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Uncertain significance
(Jul 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000211112.13
First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11093816, 21404117, 18383312, 19015241, 9833759, 15943554, 17510385, 21901500, 23741719, 34426522, 22753075, 12799449, 20533529, 31697235) (less)
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Uncertain significance
(Feb 10, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV000292212.6
First in ClinVar: Jul 08, 2016 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces isoleucine with phenylalanine at codon 565 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces isoleucine with phenylalanine at codon 565 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant causes a partial loss of mismatch repair activity of MLH1 protein (PMID: 17510385). This variant has been observed in several individuals affected with Lynch syndrome (PMID: 9833759, 15943554, 21404117, 21901500). However, a tumor sample from one of these individuals showed normal MLH1 protein expression but loss of MSH2 and MSH6 protein expression, indicating the presence of a pathogenic variant in the MSH2 gene (PMID: 15943554). In addition, one of the affected individuals carried a pathogenic MSH2 variant that could explain the observed phenotype (PMID: 21404117). This variant has been identified in 2/251154 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)
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Uncertain significance
(Jan 03, 2024)
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000543656.8
First in ClinVar: Mar 24, 2015 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 565 of the MLH1 protein (p.Ile565Phe). … (more)
This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 565 of the MLH1 protein (p.Ile565Phe). This variant is present in population databases (rs63750062, gnomAD 0.002%). This missense change has been observed in individual(s) with Lynch syndrome. However, in one of these individuals a pathogenic allele was also identified in MSH2, which suggests that this c.1693A>T variant was not the primary cause of disease. (PMID: 9833759, 21404117, 21901500). ClinVar contains an entry for this variant (Variation ID: 89842). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MLH1 protein function. Experimental studies have shown that this missense change affects MLH1 function (PMID: 17510385). 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)
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Uncertain Significance
(Jan 11, 2024)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004843196.1
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)
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Comment:
This missense variant replaces isoleucine with phenylalanine at codon 565 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces isoleucine with phenylalanine at codon 565 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant causes a partial loss of mismatch repair activity of MLH1 protein (PMID: 17510385). This variant has been observed in several individuals affected with Lynch syndrome (PMID: 9833759, 15943554, 21404117, 21901500). However, a tumor sample from one of these individuals showed normal MLH1 protein expression but loss of MSH2 and MSH6 protein expression, indicating the presence of a pathogenic variant in the MSH2 gene (PMID: 15943554). In addition, one of the affected individuals carried a pathogenic MSH2 variant that could explain the observed phenotype (PMID: 21404117). This variant has been identified in 2/251154 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: 2
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Uncertain significance
(Nov 16, 2023)
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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: SCV000662094.5
First in ClinVar: Jul 08, 2016 Last updated: May 01, 2024 |
Comment:
The p.I565F variant (also known as c.1693A>T), located in coding exon 15 of the MLH1 gene, results from an A to T substitution at nucleotide … (more)
The p.I565F variant (also known as c.1693A>T), located in coding exon 15 of the MLH1 gene, results from an A to T substitution at nucleotide position 1693. The isoleucine at codon 565 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration was detected in a proband with colorectal cancer diagnosed at age 44 as well as in another relative with colorectal cancer in a family meeting Amsterdam criteria (Hutter P et al. Int. J. Cancer. 1998 Dec;78:680-4). This alteration was detected in another individual who also carried a deletion in MSH2, and that proband's tumor that showed intact MLH1 protein expression but absent MSH2 and MSH6 proteins by IHC analysis (Hardt K et al. Fam. Cancer. 2011 Jun;10:273-84). Another study concluded that this variant was most likely not disease causing when it was detected in a Lynch-related tumor showing intact MLH1 and absent MSH2 and MSH6 proteins on IHC (Grabowski M et al. Genet. Test. 2005;9:138-46). Two Iranian patients with colorectal cancer meeting Amsterdam criteria were found to have this alteration; however, they were not tested for mutations in other MMR genes, and no IHC or MSI data was available on these tumors (Shahmoradi S et al. Fam. Cancer. 2012 Mar;11:13-7). In a study assessing the function of various MLH1 alterations, p.I565F demonstrated 52.5% of in vitro mismatch repair activity and >75% of relative MLH1 protein expression (Takahashi M et al. Cancer Res. 2007 May;67:4595-604). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Mar 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001153847.25
First in ClinVar: Feb 03, 2020 Last updated: Aug 04, 2024 |
Number of individuals with the variant: 1
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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Lynch syndrome
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001549100.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The MLH1 p.Ile565Phe variant was identified in 2 of 424 proband chromosomes (frequency: 0.005) from Swiss and German individuals or families with HNPCC (Hardt 2011, … (more)
The MLH1 p.Ile565Phe variant was identified in 2 of 424 proband chromosomes (frequency: 0.005) from Swiss and German individuals or families with HNPCC (Hardt 2011, Hutter 1998). The variant was also identified in dbSNP (ID: rs63750062) as “With Uncertain significance allele” and ClinVar (classified as uncertain significance by an InSiGHT expert panel (2013), GeneDx, Color, Invitae and Ambry Genetics). The variant was not identified in UMD-LSDB. The variant was identified in control databases in 2 of 245948 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). It was observed in the following population: European Non-Finnish in 2 of 111450 chromosomes (freq: 0.00002) but not in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, or South Asian populations. The p.Ile565 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Phe variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. One study using yeast assays, the variant showed decreased MLH1 expression at approximately 75% of wildtype and 53% in vitro MMR activity relative to wild type, but did not show a dominant mutator effect (Takahashi 2007). This variant was identified by our laboratory in a patient with an MLH1-deficient pancreatic tumour. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (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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Computational and cellular studies reveal structural destabilization and degradation of MLH1 variants in Lynch syndrome. | Abildgaard AB | eLife | 2019 | PMID: 31697235 |
Two novel mutations in hMLH1 gene in Iranian hereditary non-polyposis colorectal cancer patients. | Shahmoradi S | Familial cancer | 2012 | PMID: 21901500 |
Missense variants in hMLH1 identified in patients from the German HNPCC consortium and functional studies. | Hardt K | Familial cancer | 2011 | PMID: 21404117 |
Functional analysis of human MLH1 variants using yeast and in vitro mismatch repair assays. | Takahashi M | Cancer research | 2007 | PMID: 17510385 |
Deletions account for 17% of pathogenic germline alterations in MLH1 and MSH2 in hereditary nonpolyposis colorectal cancer (HNPCC) families. | Grabowski M | Genetic testing | 2005 | PMID: 15943554 |
Excess of hMLH1 germline mutations in Swiss families with hereditary non-polyposis colorectal cancer. | Hutter P | International journal of cancer | 1998 | PMID: 9833759 |
Text-mined citations for rs63750062 ...
HelpRecord last updated Sep 29, 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.