ClinVar Genomic variation as it relates to human health
NM_000249.4(MLH1):c.655A>G (p.Ile219Val)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000249.4(MLH1):c.655A>G (p.Ile219Val)
Variation ID: 36557 Accession: VCV000036557.44
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 37012077 (GRCh38) [ NCBI UCSC ] 3: 37053568 (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 12, 2013 Sep 29, 2024 Sep 5, 2013 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- I219V, I121V, I186V
- Other names
- -
- Canonical SPDI
- NC_000003.12:37012076: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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0.12959 (G)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.23277
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.24296
1000 Genomes Project 30x 0.12914
1000 Genomes Project 0.12959
Trans-Omics for Precision Medicine (TOPMed) 0.21422
The Genome Aggregation Database (gnomAD) 0.23048
Exome Aggregation Consortium (ExAC) 0.23254
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 |
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
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 (3) |
reviewed by expert panel
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Sep 5, 2013 | RCV000030230.16 | |
Benign (5) |
criteria provided, multiple submitters, no conflicts
|
Nov 30, 2023 | RCV000034548.25 | |
Benign (10) |
criteria provided, multiple submitters, no conflicts
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Jun 24, 2014 | RCV000035355.39 | |
Benign (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 10, 2020 | RCV000131385.14 | |
Benign (2) |
criteria provided, single submitter
|
Aug 18, 2017 | RCV000144603.10 | |
Benign (4) |
criteria provided, multiple submitters, no conflicts
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Jul 7, 2023 | RCV000614686.14 | |
Benign (1) |
criteria provided, single submitter
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Feb 1, 2024 | RCV001083425.13 | |
Benign (1) |
no assertion criteria provided
|
- | RCV001269359.9 |
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)
|
reviewed by expert panel
Method: research
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Lynch Syndrome
Affected status: unknown
Allele origin:
germline
|
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
Accession: SCV000106807.3
First in ClinVar: Dec 19, 2013 Last updated: Dec 24, 2022
Comment:
Classified with v1.9 guidelines: https://docs.google.com/file/d/0B3JL6rP6JzhoN2EydHRVMEI1UGs
|
Comments (2):
MAF >1%
Converted during submission to Benign.
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Benign
(Nov 04, 2014)
|
criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000292085.1
First in ClinVar: Jul 08, 2016 Last updated: Jul 08, 2016 |
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Benign
(-)
|
criteria provided, single submitter
Method: clinical testing
|
NOT SPECIFIED
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV000303152.1
First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016 |
|
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Benign
(Aug 18, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome 1
Affected status: no
Allele origin:
germline
|
IntelligeneCG
Accession: SCV000611716.1
First in ClinVar: Oct 19, 2014 Last updated: Oct 19, 2014 |
|
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Benign
(Nov 01, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Colorectal cancer, hereditary nonpolyposis, type 2
Affected status: yes
Allele origin:
germline
|
Center for Human Genetics, Inc, Center for Human Genetics, Inc
Accession: SCV000781752.1
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
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Benign
(Jun 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
|
Eurofins Ntd Llc (ga)
Accession: SCV000110268.8
First in ClinVar: Jan 17, 2014 Last updated: May 03, 2018 |
Number of individuals with the variant: 14
Sex: mixed
|
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Benign
(Aug 23, 2011)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000059003.5
First in ClinVar: May 03, 2013 Last updated: Aug 27, 2017 |
Comment:
This variant is classified as benign based on its high frequency in the general population (rs1799977, MAF >3%).
Number of individuals with the variant: 2
|
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Benign
(Mar 06, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Colorectal cancer, hereditary nonpolyposis, type 2
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000443330.3
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
(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: SCV001875389.1
First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021 |
Comment:
This variant is associated with the following publications: (PMID: 24595079, 15918206, 30998989, 28932927, 24728327, 27173243, 27153395, 7704024, 27487738, 9032648, 20336543, 23760103, 20981092, 9697702, 24689082, 22753075, … (more)
This variant is associated with the following publications: (PMID: 24595079, 15918206, 30998989, 28932927, 24728327, 27173243, 27153395, 7704024, 27487738, 9032648, 20336543, 23760103, 20981092, 9697702, 24689082, 22753075, 22949387, 21120944, 17594722, 11555625, 19371218, 22283331, 21239990, 11781295, 16083711, 21136174, 20149637, 19665066, 23403630, 16982745, 17510385, 12810663, 18547406, 19863800, 21615986, 23060557, 22703879, 20860725) (less)
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Benign
(Jan 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
|
Sema4, Sema4
Accession: SCV002528766.1
First in ClinVar: Mar 25, 2020 Last updated: Mar 25, 2020 |
|
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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
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000999981.5
First in ClinVar: Dec 17, 2019 Last updated: Feb 20, 2024 |
|
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Benign
(Nov 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000604227.9
First in ClinVar: Aug 27, 2017 Last updated: Feb 20, 2024 |
|
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Benign
(Nov 13, 2014)
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criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000186361.8
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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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
|
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Accession: SCV004015862.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
|
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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
|
All of Us Research Program, National Institutes of Health
Accession: SCV004840890.1
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: 50191
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Benign
(-)
|
criteria provided, single submitter
Method: not provided
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not provided
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Breakthrough Genomics, Breakthrough Genomics
Accession: SCV005245161.1
First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024 |
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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: SCV000189930.1
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
|
Breast Cancer
Affected status: yes
Allele origin:
germline
|
Center of Medical Genetics and Primary Health Care
Accession: SCV001448700.1
First in ClinVar: Dec 07, 2020 Last updated: Dec 07, 2020 |
|
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Benign
(-)
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no assertion criteria provided
Method: clinical testing
|
not specified
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: SCV000592366.2 First in ClinVar: Aug 27, 2017 Last updated: Jan 26, 2021 |
Comment:
The p.Ile219Val variant is not expected to have clinical significance because this residue is not well conserved and the variant amino acid Val (valine) at … (more)
The p.Ile219Val variant is not expected to have clinical significance because this residue is not well conserved and the variant amino acid Val (valine) at position 219 is present in frog and zebrafish. In addition, this variant is listed in dbSNP as a common polymorphism (dbSNP#:rs1799977). (less)
Number of individuals with the variant: 36
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Benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
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: SCV001969492.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
|
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no known pathogenicity
(Jul 13, 2012)
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no assertion criteria provided
Method: research
|
not provided
Affected status: no
Allele origin:
germline
|
Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Study: ClinSeq
Accession: SCV000043321.1 First in ClinVar: Apr 12, 2013 Last updated: Apr 12, 2013 |
Comment:
Converted during submission to Benign.
Number of individuals with the variant: 288
Comment on evidence:
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for … (more)
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for details. (less)
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Benign
(Nov 15, 2011)
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no assertion criteria provided
Method: clinical testing
|
Lynch syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000052897.2
First in ClinVar: Apr 04, 2013 Last updated: Mar 24, 2015 |
|
|
Benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
unknown
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000257110.2
First in ClinVar: Nov 20, 2015 Last updated: Aug 27, 2017 |
|
|
Benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
Colorectal cancer, hereditary nonpolyposis, type 2
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV000734264.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
|
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Benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
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: SCV001906103.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
|
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Benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001919475.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
|
|
Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001927690.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
|
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Benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
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: SCV001958956.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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not provided
(Sep 19, 2013)
|
no classification provided
Method: reference population
|
AllHighlyPenetrant
Affected status: unknown
Allele origin:
germline
|
ITMI
Accession: SCV000085536.1
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014
Comment:
Please see associated publication for description of ethnicities
|
Observation 1:
Ethnicity/Population group: Whole_cohort
Observation 2:
Ethnicity/Population group: African
Observation 3:
Ethnicity/Population group: African_European
Observation 4:
Ethnicity/Population group: Central_Asian
Observation 5:
Ethnicity/Population group: East_Asian
Observation 6:
Ethnicity/Population group: European
Observation 7:
Ethnicity/Population group: Hispanic
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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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http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MLH1 | - | - | - | - |
http://www.insight-database.org/classifications/index.html?gene=MLH1&variant=c.655A%3EG | - | - | - | - |
Text-mined citations for rs1799977 ...
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.