ClinVar Genomic variation as it relates to human health
NM_000249.4(MLH1):c.1558+14G>A
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.1558+14G>A
Variation ID: 36541 Accession: VCV000036541.42
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 37028946 (GRCh38) [ NCBI UCSC ] 3: 37070437 (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 Apr 4, 2013 May 1, 2024 Sep 5, 2013 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- Other names
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- Canonical SPDI
- NC_000003.12:37028945:G:A
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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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0.05012 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.03661
Exome Aggregation Consortium (ExAC) 0.03948
1000 Genomes Project 30x 0.04981
1000 Genomes Project 0.05012
The Genome Aggregation Database (gnomAD) 0.05554
Trans-Omics for Precision Medicine (TOPMed) 0.05557
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.05874
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
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. |
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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. |
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Benign (2) |
reviewed by expert panel
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Sep 5, 2013 | RCV000030214.16 | |
Benign (9) |
criteria provided, multiple submitters, no conflicts
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Aug 15, 2023 | RCV000078416.38 | |
Benign (1) |
no assertion criteria provided
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Jul 24, 2014 | RCV000144605.9 | |
Benign (2) |
criteria provided, multiple submitters, no conflicts
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Nov 26, 2014 | RCV000449421.12 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Jul 7, 2023 | RCV000616483.16 | |
Benign (1) |
no assertion criteria provided
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- | RCV001354017.9 | |
Benign (1) |
criteria provided, single submitter
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Feb 1, 2024 | RCV001510183.13 | |
Benign (2) |
criteria provided, multiple submitters, no conflicts
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Nov 29, 2023 | RCV001650849.18 |
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. |
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no known pathogenicity
(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: SCV000106241.3
First in ClinVar: Dec 19, 2013 Last updated: Dec 24, 2022
Comment:
Classified with v1.9 guidelines: https://docs.google.com/file/d/0B3JL6rP6JzhoN2EydHRVMEI1UGs
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Comments (2):
MAF >1%
Converted during submission to Benign.
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Benign
(Nov 26, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV000537353.1
First in ClinVar: Mar 25, 2017 Last updated: Mar 25, 2017 |
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benign
(Aug 18, 2011)
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criteria provided, single submitter
Method: clinical testing
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Hereditary non-polyposis colon cancer
(autosomal unknown)
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000052881.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 11, 2022 |
Comment:
Converted during submission to Benign.
Observation 1:
Tissue: Blood
Observation 2:
Tissue: Blood
Observation 3:
Tissue: Blood
Observation 4:
Tissue: Blood
Observation 5:
Tissue: Blood
Observation 6:
Tissue: Blood
Observation 7:
Tissue: Blood
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Benign
(Feb 01, 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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Invitae
Accession: SCV001717148.3
First in ClinVar: Jun 15, 2021 Last updated: Feb 14, 2024 |
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Benign
(Nov 18, 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: SCV002704389.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more)
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Benign
(-)
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criteria provided, single submitter
Method: clinical testing
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NOT SPECIFIED
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV000303145.1
First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016 |
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Uncertain significance
(Nov 01, 2016)
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criteria provided, single submitter
Method: clinical testing
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Colorectal cancer, hereditary nonpolyposis, type 2
Affected status: yes
Allele origin:
germline
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Center for Human Genetics, Inc, Center for Human Genetics, Inc
Accession: SCV000781758.1
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
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Benign
(Jan 14, 2013)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000110262.8
First in ClinVar: Jan 17, 2014 Last updated: Aug 27, 2017 |
Number of individuals with the variant: 3
Sex: mixed
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Benign
(Mar 06, 2018)
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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:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000443337.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
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Benign
(Jul 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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Colorectal cancer, hereditary nonpolyposis, type 2
Affected status: yes
Allele origin:
germline
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KCCC/NGS Laboratory, Kuwait Cancer Control Center
Accession: SCV004015866.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
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Benign
(Nov 29, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001156601.5
First in ClinVar: Feb 10, 2020 Last updated: Feb 20, 2024 |
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Benign
(Mar 03, 2015)
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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: SCV001868837.1
First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021 |
Comment:
This variant is associated with the following publications: (PMID: 28932927, 27629256, 27884173, 15996210, 24689082, 23588873, 16395668)
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Benign
(Aug 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002552493.4
First in ClinVar: Jul 30, 2022 Last updated: Aug 18, 2023 |
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Benign
(-)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001965035.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Benign
(Jul 24, 2014)
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no assertion criteria provided
Method: clinical testing
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Lynch syndrome I
Affected status: unknown
Allele origin:
germline
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Pathway Genomics
Accession: SCV000189932.1
First in ClinVar: Oct 19, 2014 Last updated: Oct 19, 2014 |
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Benign
(-)
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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: SCV000592408.2 First in ClinVar: Aug 27, 2017 Last updated: Apr 13, 2021 |
Comment:
The c.1558+14G>A variant has been identified in 10 out of 670 proband chromosomes (frequency 0.015) in individuals with colorectal and breast cancer as well as … (more)
The c.1558+14G>A variant has been identified in 10 out of 670 proband chromosomes (frequency 0.015) in individuals with colorectal and breast cancer as well as the transitional cell carcinoma of the urinary tract; however no normal population controls were included in these studies (Furihata 2001, Kurzawski 2002, Murata 2002, Palicio 2002, Ward 2002, Lee 2005). It is listed in dbSNP database presented “With non-pathogenic allele” (ID#: rs41562513) with a “global minor allele frequency of 0.054 (1000 genomes), therefore increasing the likelihood that this variant is benign. One study demonstrated by RT-PCR that this variant did not affect splicing (Auclari_2006_16395668), increasing the likelihood this variant does not have clinical significance. This variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions, or positions +3 to +6 that are part of the splicing consensus sequence which sometimes affect splicing. In addition, in-silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predicts no change in the splice site prediction score. In summary, based on the above information, this variant is classified as benign (less)
Number of individuals with the variant: 12
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Benign
(-)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001906015.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Benign
(-)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001919830.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Benign
(-)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001956792.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Benign
(-)
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no assertion criteria provided
Method: research
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not specified
Affected status: unknown
Allele origin:
unknown
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000257053.1
First in ClinVar: Nov 20, 2015 Last updated: Nov 20, 2015 |
Number of individuals with the variant: 32
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Benign
(-)
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no assertion criteria provided
Method: clinical testing
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Colorectal cancer, hereditary nonpolyposis, type 2
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV000734267.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
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Benign
(-)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Study: VKGL Data-share Consensus
Accession: SCV001798604.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
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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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Genetic and epigenetic modification of mismatch repair genes hMSH2 and hMLH1 in sporadic breast cancer with microsatellite instability. | Murata H | Oncogene | 2002 | PMID: 12173039 |
Mismatch repair gene analysis in Catalonian families with colorectal cancer. | Palicio M | Journal of medical genetics | 2002 | PMID: 12070261 |
Microsatellite instability and mismatch repair gene inactivation in sporadic pancreatic and colon tumours. | Ghimenti C | British journal of cancer | 1999 | PMID: 10389971 |
Mutation screening in the hMLH1 gene in Swedish hereditary nonpolyposis colon cancer families. | Tannergård P | Cancer research | 1995 | PMID: 8521398 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MLH1 | - | - | - | - |
http://www.insight-database.org/classifications/index.html?gene=MLH1&variant=c.1558%2B14G%3EA | - | - | - | - |
Text-mined citations for rs41562513 ...
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.