ClinVar Genomic variation as it relates to human health
NM_000249.4(MLH1):c.1588_1590del (p.Phe530del)
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.1588_1590del (p.Phe530del)
Variation ID: 89798 Accession: VCV000089798.8
- Type and length
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Deletion, 3 bp
- Location
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Cytogenetic: 3p22.2 3: 37040214-37040216 (GRCh38) [ NCBI UCSC ] 3: 37081705-37081707 (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
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Nucleotide Protein Molecular
consequenceNM_000249.4:c.1588_1590del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000240.1:p.Phe530del inframe deletion NM_000249.3:c.1588_1590delTTC NM_001167617.3:c.1294_1296del NP_001161089.1:p.Phe432del inframe deletion NM_001167618.3:c.865_867del NP_001161090.1:p.Phe289del inframe deletion NM_001167619.3:c.865_867del NP_001161091.1:p.Phe289del inframe deletion NM_001258271.2:c.1588_1590del NP_001245200.1:p.Phe530del inframe deletion NM_001258273.2:c.865_867del NP_001245202.1:p.Phe289del inframe deletion NM_001258274.3:c.865_867del NP_001245203.1:p.Phe289del inframe deletion NM_001354615.2:c.865_867del NP_001341544.1:p.Phe289del inframe deletion NM_001354616.2:c.865_867del NP_001341545.1:p.Phe289del inframe deletion NM_001354617.2:c.865_867del NP_001341546.1:p.Phe289del inframe deletion NM_001354618.2:c.865_867del NP_001341547.1:p.Phe289del inframe deletion NM_001354619.2:c.865_867del NP_001341548.1:p.Phe289del inframe deletion NM_001354620.2:c.1294_1296del NP_001341549.1:p.Phe432del inframe deletion NM_001354621.2:c.565_567del NP_001341550.1:p.Phe189del inframe deletion NM_001354622.2:c.565_567del NP_001341551.1:p.Phe189del inframe deletion NM_001354623.2:c.565_567del NP_001341552.1:p.Phe189del inframe deletion NM_001354624.2:c.514_516del NP_001341553.1:p.Phe172del inframe deletion NM_001354625.2:c.514_516del NP_001341554.1:p.Phe172del inframe deletion NM_001354626.2:c.514_516del NP_001341555.1:p.Phe172del inframe deletion NM_001354627.2:c.514_516del NP_001341556.1:p.Phe172del inframe deletion NM_001354628.2:c.1588_1590del NP_001341557.1:p.Phe530del inframe deletion NM_001354629.2:c.1489_1491del NP_001341558.1:p.Phe497del inframe deletion NM_001354630.2:c.1588_1590del NP_001341559.1:p.Phe530del inframe deletion NC_000003.12:g.37040215_37040217del NC_000003.11:g.37081706_37081708del NG_007109.2:g.51866_51868del LRG_216:g.51866_51868del - Protein change
- F530del, F432del, F497del, F172del, F289del, F189del
- Other names
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- Canonical SPDI
- NC_000003.12:37040213:CTTC: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
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
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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
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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Pathogenic (1) |
reviewed by expert panel
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Sep 5, 2013 | RCV000075272.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Feb 17, 2014 | RCV000130099.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Aug 6, 2020 | RCV001344767.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Sep 22, 2023 | RCV003466956.1 |
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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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: SCV000106266.3
First in ClinVar: Dec 19, 2013 Last updated: Dec 24, 2022 |
Comment:
Multifactorial likelihood analysis posterior probability >0.99
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Likely pathogenic
(Sep 22, 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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Baylor Genetics
Accession: SCV004195100.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Uncertain significance
(Aug 06, 2020)
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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: SCV001538844.3
First in ClinVar: Mar 22, 2021 Last updated: Feb 14, 2024 |
Comment:
Based on a multifactorial likelihood algorithm using genetic data, this variant has been determined to have a high probability of being pathogenic (PMID: 24362816). This … (more)
Based on a multifactorial likelihood algorithm using genetic data, this variant has been determined to have a high probability of being pathogenic (PMID: 24362816). This variant has been observed in individual(s) with an increased risk for, or a diagnosis of Lynch syndrome (PMID: 15786548, 28514183). ClinVar contains an entry for this variant (Variation ID: 89798). This variant is not present in population databases (ExAC no frequency). This variant, c.1588_1590del, results in the deletion of 1 amino acid(s) of the MLH1 protein (p.Phe530del), but otherwise preserves the integrity of the reading frame. 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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Likely pathogenic
(Feb 17, 2014)
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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: SCV000184929.6
First in ClinVar: Aug 06, 2014 Last updated: Mar 24, 2015 |
Comment:
The c.1588_1590delTTC variant (also known as p.F530del) is located in coding exon 14 of the MLH1 gene. This variant results from an in-frame deletion of … (more)
The c.1588_1590delTTC variant (also known as p.F530del) is located in coding exon 14 of the MLH1 gene. This variant results from an in-frame deletion of 3 nucleotides at positions 1588 to 1590 and causes the removal of a highly-conserved phenylalanine residue at codon 1530. This alteration has been described as a pathogenic mutation in Chinese family satisfying Amsterdam criteria for HNPCC/Lynch syndrome (Luo D et al. World J Gastroenterol. 2005 Mar 21;11(11):1673-9). The c.1588_1590delTTC alteration was detected in three family members diagnosed with early-onset CRC (proband and two sons) and was associated with microsatellite instability, but normal MLH1 staining in tumor tissues. This alteration has been classified as definitely pathogenic (p>0.99) by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Thompson B et al. Nat Genet. 2014 Feb;46(2):107-15). This variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. To date, this alteration has been detected with an allele frequency of approximately 0.01% (greater than 13000 alleles tested) in our clinical cohort (includes this individual). Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
Number of individuals with the variant: 1
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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 |
Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database. | Thompson BA | Nature genetics | 2014 | PMID: 24362816 |
Clinicopathological and molecular genetic analysis of HNPCC in China. | Luo DC | World journal of gastroenterology | 2005 | PMID: 15786548 |
[Mutation analysis of hMSH2 and hMLH1 genes in Chinese hereditary nonpolyposis colorectal cancer families]. | Cai Q | Zhonghua bing li xue za zhi = Chinese journal of pathology | 2003 | PMID: 14514376 |
http://www.insight-database.org/classifications/index.html?gene=MLH1&variant=c.1588_1590del | - | - | - | - |
Text-mined citations for rs587778930 ...
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.