ClinVar Genomic variation as it relates to human health
NM_000249.4(MLH1):c.1852A>G (p.Lys618Glu)
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(1); Benign(5); Likely benign(11)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000249.4(MLH1):c.1852A>G (p.Lys618Glu)
Variation ID: 89903 Accession: VCV000089903.66
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 37047639 (GRCh38) [ NCBI UCSC ] 3: 37089130 (GRCh37) [ NCBI UCSC ] 3: 37064134 (NCBI36) [ 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 24, 2014 Oct 8, 2024 Aug 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000249.4:c.1852A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000240.1:p.Lys618Glu missense NM_001167617.3:c.1558A>G NP_001161089.1:p.Lys520Glu missense NM_001167618.3:c.1129A>G NP_001161090.1:p.Lys377Glu missense NM_001167619.3:c.1129A>G NP_001161091.1:p.Lys377Glu missense NM_001258271.2:c.1852A>G NP_001245200.1:p.Lys618Glu missense NM_001258273.2:c.1129A>G NP_001245202.1:p.Lys377Glu missense NM_001258274.3:c.1129A>G NP_001245203.1:p.Lys377Glu missense NM_001354615.2:c.1129A>G NP_001341544.1:p.Lys377Glu missense NM_001354616.2:c.1129A>G NP_001341545.1:p.Lys377Glu missense NM_001354617.2:c.1129A>G NP_001341546.1:p.Lys377Glu missense NM_001354618.2:c.1129A>G NP_001341547.1:p.Lys377Glu missense NM_001354619.2:c.1129A>G NP_001341548.1:p.Lys377Glu missense NM_001354620.2:c.1558A>G NP_001341549.1:p.Lys520Glu missense NM_001354621.2:c.829A>G NP_001341550.1:p.Lys277Glu missense NM_001354622.2:c.829A>G NP_001341551.1:p.Lys277Glu missense NM_001354623.2:c.829A>G NP_001341552.1:p.Lys277Glu missense NM_001354624.2:c.778A>G NP_001341553.1:p.Lys260Glu missense NM_001354625.2:c.778A>G NP_001341554.1:p.Lys260Glu missense NM_001354626.2:c.778A>G NP_001341555.1:p.Lys260Glu missense NM_001354627.2:c.778A>G NP_001341556.1:p.Lys260Glu missense NM_001354628.2:c.1852A>G NP_001341557.1:p.Lys618Glu missense NM_001354629.2:c.1753A>G NP_001341558.1:p.Lys585Glu missense NM_001354630.2:c.1732-878A>G intron variant NC_000003.12:g.37047639A>G NC_000003.11:g.37089130A>G NC_000003.10:g.37064134A>G NG_007109.2:g.59290A>G LRG_216:g.59290A>G LRG_216t1:c.1852A>G LRG_216p1:p.Lys618Glu - Protein change
- K618E, K260E, K520E, K585E, K277E, K377E
- Other names
- -
- Canonical SPDI
- NC_000003.12:37047638:A:G
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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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0.00319 (G)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00297
1000 Genomes Project 0.00319
Exome Aggregation Consortium (ExAC) 0.00342
The Genome Aggregation Database (gnomAD), exomes 0.00348
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00369
The Genome Aggregation Database (gnomAD) 0.00399
Trans-Omics for Precision Medicine (TOPMed) 0.00401
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 |
5689 | 5749 |
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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Likely benign (4) |
criteria provided, multiple submitters, no conflicts
|
Aug 1, 2024 | RCV000114852.31 | |
Benign/Likely benign (4) |
criteria provided, multiple submitters, no conflicts
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Nov 22, 2022 | RCV000132423.14 | |
Benign/Likely benign (5) |
criteria provided, multiple submitters, no conflicts
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Aug 15, 2023 | RCV000174992.21 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Mar 15, 2023 | RCV000663286.11 | |
Benign (1) |
criteria provided, single submitter
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Jan 30, 2024 | RCV001083570.9 | |
Likely benign (1) |
criteria provided, single submitter
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Jun 22, 2023 | RCV003149734.5 | |
Likely benign (1) |
criteria provided, single submitter
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Feb 5, 2024 | RCV003997118.2 |
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. |
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Likely benign
(Mar 28, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000539633.1
First in ClinVar: Nov 20, 2015 Last updated: Nov 20, 2015 |
Comment:
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or … (more)
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 1 report in HGMD; ExAC: 0.5% (358/66740) European chromosomes (less)
Method: Genome/Exome Filtration
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Likely benign
(Apr 03, 2017)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000595803.1
First in ClinVar: Nov 20, 2015 Last updated: Nov 20, 2015 |
|
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Likely benign
(May 23, 2018)
|
criteria provided, single submitter
Method: clinical testing
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Colorectal cancer, hereditary nonpolyposis, type 2
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000786528.2
First in ClinVar: Jul 15, 2018 Last updated: Jul 15, 2018 |
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Likely benign
(Sep 24, 2014)
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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: SCV000226408.5
First in ClinVar: Jun 28, 2015 Last updated: May 30, 2018 |
Number of individuals with the variant: 3
Sex: mixed
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Likely benign
(Jun 10, 2019)
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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
|
Illumina Laboratory Services, Illumina
Accession: SCV001305810.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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Uncertain significance
(Mar 15, 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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Myriad Genetics, Inc.
Accession: SCV004018161.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
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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: SCV002550866.3
First in ClinVar: Jul 27, 2022 Last updated: Aug 18, 2023 |
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Likely benign
(Jun 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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Breast and/or ovarian cancer
Affected status: unknown
Allele origin:
germline
|
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV003838870.2
First in ClinVar: Mar 11, 2023 Last updated: Feb 04, 2024 |
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Likely Benign
(Feb 05, 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: SCV004843225.1
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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Number of individuals with the variant: 1048
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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: SCV000187516.8
First in ClinVar: Aug 06, 2014 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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Likely benign
(May 28, 2019)
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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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Mendelics
Accession: SCV001136425.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Benign
(May 10, 2020)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002528687.1
First in ClinVar: Mar 25, 2020 Last updated: Mar 25, 2020 |
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Likely benign
(Jan 02, 2015)
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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: SCV000689843.2
First in ClinVar: Feb 19, 2018 Last updated: Dec 11, 2022 |
|
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Benign
(Nov 22, 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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Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Accession: SCV002819229.1
First in ClinVar: Jan 15, 2023 Last updated: Jan 15, 2023 |
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Benign
(Jan 30, 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: SCV000555963.7
First in ClinVar: Mar 24, 2015 Last updated: Feb 28, 2024 |
|
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Likely benign
(-)
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criteria provided, single submitter
Method: not provided
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not provided
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Breakthrough Genomics, Breakthrough Genomics
Accession: SCV005258451.1
First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024 |
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Likely benign
(Aug 01, 2024)
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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: SCV000575343.31
First in ClinVar: Feb 24, 2015 Last updated: Oct 08, 2024 |
Comment:
MLH1: PM5, BS2
Number of individuals with the variant: 14
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Uncertain significance
(-)
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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: SCV000257070.1
First in ClinVar: Nov 20, 2015 Last updated: Nov 20, 2015 |
Number of individuals with the variant: 2
|
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
|
not provided
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: SCV001553065.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
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not provided
(-)
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no classification provided
Method: not provided
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not provided
Affected status: not provided
Allele origin:
unknown
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Harris Lab, University of Minnesota
Accession: SCV000148747.1
First in ClinVar: Apr 24, 2014 Last updated: Apr 24, 2014 |
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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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Expanding the genotype-phenotype spectrum in hereditary colorectal cancer by gene panel testing. | Rohlin A | Familial cancer | 2017 | PMID: 27696107 |
The MLH1 c.1852_1853delinsGC (p.K618A) variant in colorectal cancer: genetic association study in 18,723 individuals. | Abulí A | PloS one | 2014 | PMID: 24743384 |
Expression defect size among unclassified MLH1 variants determines pathogenicity in Lynch syndrome diagnosis. | Hinrichsen I | Clinical cancer research : an official journal of the American Association for Cancer Research | 2013 | PMID: 23403630 |
Prioritization of candidate SNPs in colon cancer using bioinformatics tools: an alternative approach for a cancer biologist. | George Priya Doss C | Interdisciplinary sciences, computational life sciences | 2010 | PMID: 21153778 |
Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). | Hampel H | The New England journal of medicine | 2005 | PMID: 15872200 |
Genetic testing is important in families with a history suggestive of hereditary non-polyposis colorectal cancer even if the Amsterdam criteria are not fulfilled. | Beck NE | The British journal of surgery | 1997 | PMID: 9052445 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MLH1 | - | - | - | - |
Text-mined citations for rs35001569 ...
HelpRecord last updated Oct 13, 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.