ClinVar Genomic variation as it relates to human health
NM_000249.4(MLH1):c.55A>T (p.Ile19Phe)
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.55A>T (p.Ile19Phe)
Variation ID: 90274 Accession: VCV000090274.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 36993602 (GRCh38) [ NCBI UCSC ] 3: 37035093 (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 20, 2024 Jun 13, 2018 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- I19F
- Other names
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- Canonical SPDI
- NC_000003.12:36993601: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.
Trans-Omics for Precision Medicine (TOPMed) 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 |
- | 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
Help
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) |
no assertion criteria provided
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- | RCV000075763.5 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Feb 10, 2023 | RCV000162610.6 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Sep 1, 2020 | RCV000483320.3 | |
Pathogenic (1) |
reviewed by expert panel
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Jun 13, 2018 | RCV000680175.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 29, 2023 | RCV000791372.5 |
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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Pathogenic
(Jun 13, 2018)
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reviewed by expert panel
Method: curation
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Lynch syndrome 1
Affected status: yes
Allele origin:
germline
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International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
Accession: SCV000106771.4
First in ClinVar: Dec 19, 2013 Last updated: Dec 11, 2022 |
Comment:
Multifactorial likelihood analysis posterior probability > 0.95 (0.997)
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Likely pathogenic
(Feb 10, 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: SCV000213038.7
First in ClinVar: Mar 24, 2015 Last updated: Apr 15, 2023 |
Comment:
The p.I19F variant (also known as c.55A>T), located in coding exon 1 of the MLH1 gene, results from an A to T substitution at nucleotide … (more)
The p.I19F variant (also known as c.55A>T), located in coding exon 1 of the MLH1 gene, results from an A to T substitution at nucleotide position 55. The isoleucine at codon 19 is replaced by phenylalanine, an amino acid with similar properties. This alteration has been identified in multiple individuals with Lynch syndrome-related cancers whose families were either suspicious for Lynch syndrome or met Amsterdam criteria (Andrew SE et al. Genet.Test. 2002;6(4):319-22; Kurzawski G et al. J. Med. Genet. 2002 Oct;39:e65; Perera S et al. J. Molec. Diagnost. 2010 Nov;12(6):757-764; Yurgelun MB et al. J. Clin. Oncol. 2017 Apr;35(10):1086-1095). Protein functional analysis using a yeast-human hybrid assay demonstrated reduced mismatch repair function for this variant (Ellison AR et al. Nucleic Acids Res. 2004 Oct;32(18):5321-38). A family study conducted in our laboratory demonstrated segregation with disease for four affected individuals across two generations. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Pathogenic
(Jun 29, 2023)
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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: SCV000543595.7
First in ClinVar: Mar 24, 2015 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects MLH1 function (PMID: 15475387). Advanced modeling … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects MLH1 function (PMID: 15475387). 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 expected to disrupt MLH1 protein function. ClinVar contains an entry for this variant (Variation ID: 90274). This missense change has been observed in individuals with clinical features of Lynch syndrome and/or colorectal cancer (PMID: 12362047, 12537657, 20864636, 28135145, 28514183, 31857677). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 19 of the MLH1 protein (p.Ile19Phe). (less)
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Likely pathogenic
(Sep 01, 2020)
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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: SCV000565139.4
First in ClinVar: Apr 29, 2017 Last updated: Apr 17, 2019 |
Comment:
Observed in individuals with colorectal or other Lynch-associated cancers meeting revised Bethesda or Amsterdam II criteria (Andrew 2002, Kurzawski 2002, Perera 2010, Yurgleun 2017); Not … (more)
Observed in individuals with colorectal or other Lynch-associated cancers meeting revised Bethesda or Amsterdam II criteria (Andrew 2002, Kurzawski 2002, Perera 2010, Yurgleun 2017); Not observed in large population cohorts (Lek 2016); Published functional studies demonstrate partial loss of mismatch repair function (Ellison 2004); 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: 18383312, 30212499, 15475387, 29478780, 20864636, 12362047, 12537657, 28135145, 26333163, 26248088, 31857677, 31391288) (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Carcinoma of colon
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: SCV000592328.2 First in ClinVar: Mar 24, 2015 Last updated: Apr 13, 2021 |
Comment:
The p.Ile19Phe variant has been previously identified in 3 of 102 probands with colorectal or endometrial cancer (Kurzawski 2002, Andrew 2002, Perera 2010). In one … (more)
The p.Ile19Phe variant has been previously identified in 3 of 102 probands with colorectal or endometrial cancer (Kurzawski 2002, Andrew 2002, Perera 2010). In one study, this variant was demonstrated to segregate with colon cancer in two individuals, increasing the likelihood this variant is pathogenic (Andrew 2002). In addition, this variant was previously identified in 1 family from our laboratory with a striking history of Lynch syndrome related tumors, three affected individuals with the variant, and in 5 other affected individuals who were not tested for the variant (but at least two are obligate carriers). MSI-H tumor was demonstrated in several of these individuals but MLH1 was shown to be intact by IHC. A second family was also identified by our laboratory and this variant was shown to segregate with disease in 2 affected individuals and the tumours analyzed were demonstrated to be MSI high. In addition, the p.Ile19 residue is conserved across mammals and lower species and in-silico data (AlignGVGD, SIFT) suggest this alteration may impact the protein. However, this information is not predictive enough to determine pathogenicity. This variant is listed in dbSNP (ID#: rs63750648) as coming from a "Clinical Source" with no frequency information and is not informative for assessing its frequency in the population. In summary, based on the above evidence this variant meets our laboratory's criteria to be classified as pathogenic. (less)
Number of individuals with the variant: 12
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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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Characterization and Clinical Outcomes of DNA Mismatch Repair-deficient Small Bowel Adenocarcinoma. | Latham A | Clinical cancer research : an official journal of the American Association for Cancer Research | 2021 | PMID: 33199489 |
Retained mismatch repair protein expression occurs in approximately 6% of microsatellite instability-high cancers and is associated with missense mutations in mismatch repair genes. | Hechtman JF | Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc | 2020 | PMID: 31857677 |
A Bayesian framework for efficient and accurate variant prediction. | Qian D | PloS one | 2018 | PMID: 30212499 |
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 |
Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer. | Yurgelun MB | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2017 | PMID: 28135145 |
Classification of Amino Acid Substitutions in Mismatch Repair Proteins Using PON-MMR2. | Niroula A | Human mutation | 2015 | PMID: 26333163 |
A novel and rapid method of determining the effect of unclassified MLH1 genetic variants on differential allelic expression. | Perera S | The Journal of molecular diagnostics : JMD | 2010 | PMID: 20864636 |
Human MutL homolog (MLH1) function in DNA mismatch repair: a prospective screen for missense mutations in the ATPase domain. | Ellison AR | Nucleic acids research | 2004 | PMID: 15475387 |
An intronic polymorphism of the hMLH1 gene contributes toward incomplete genetic testing for HNPCC. | Andrew SE | Genetic testing | 2002 | PMID: 12537657 |
Germline MSH2 and MLH1 mutational spectrum in HNPCC families from Poland and the Baltic States. | Kurzawski G | Journal of medical genetics | 2002 | PMID: 12362047 |
http://www.insight-database.org/classifications/?gene=MLH1&variant=c.55A%3ET | - | - | - | - |
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Text-mined citations for rs63750648 ...
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.