ClinVar Genomic variation as it relates to human health
NM_000249.4(MLH1):c.303T>G (p.Gly101=)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000249.4(MLH1):c.303T>G (p.Gly101=)
Variation ID: 90140 Accession: VCV000090140.36
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 37001050 (GRCh38) [ NCBI UCSC ] 3: 37042541 (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 Jun 9, 2014 May 1, 2024 Sep 5, 2013 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- Other names
- p.G101G:GGT>GGG
- Canonical SPDI
- NC_000003.12:37001049:T: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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0.00639 (G)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00010
The Genome Aggregation Database (gnomAD), exomes 0.00249
Exome Aggregation Consortium (ExAC) 0.00273
1000 Genomes Project 0.00639
1000 Genomes Project 30x 0.00640
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 |
5624 | 5679 |
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 (2) |
reviewed by expert panel
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Sep 5, 2013 | RCV000075626.12 | |
Benign/Likely benign (6) |
criteria provided, multiple submitters, no conflicts
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Aug 15, 2023 | RCV000121356.13 | |
Benign (2) |
criteria provided, multiple submitters, no conflicts
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Oct 23, 2019 | RCV000160567.11 | |
Benign/Likely benign (3) |
criteria provided, multiple submitters, no conflicts
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Feb 4, 2022 | RCV000587630.13 | |
Benign (1) |
criteria provided, single submitter
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Feb 1, 2024 | RCV001084168.7 | |
Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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Jul 7, 2023 | RCV001094909.6 | |
Benign (1) |
criteria provided, single submitter
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Sep 14, 2021 | RCV003149738.2 |
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
(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: SCV000106628.3
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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Comment:
Synonymous substitution with no effect on splicing & MAF 0.01-1%
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Likely benign
(Jun 15, 2016)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000595799.1
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014 |
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Benign
(Aug 15, 2014)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000211152.10
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014 |
Comment:
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more)
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
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Likely benign
(Feb 22, 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
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Illumina Laboratory Services, Illumina
Accession: SCV000443325.3
First in ClinVar: Dec 06, 2016 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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Benign
(Apr 23, 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: SCV000684815.2
First in ClinVar: Feb 19, 2018 Last updated: Dec 11, 2022 |
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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: SCV000166253.12
First in ClinVar: Jun 23, 2014 Last updated: Feb 20, 2024 |
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Benign
(Oct 23, 2019)
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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: SCV000212812.7
First in ClinVar: Mar 24, 2015 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
(May 20, 2016)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000696159.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The c.303T>G (p.Gly101=) in MLH1 gene is a synonymous change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant … (more)
Variant summary: The c.303T>G (p.Gly101=) in MLH1 gene is a synonymous change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant does not affect normal splicing which was supported by a RNA-based functional assay by Thompson et al (2012). The variant is present in the control population dataset of ExAC at frequency of 0.0027 (331/121138) predominantly in individuals of South Asian descent (0.02; 329/16482 chrs) including 5 homozygous occurrences, suggesting that it is a polymorphism mainly found in South Asian population. The variant of interest been reported in affected individuals in whom either another known pathogenic variant was identified (Internal LCA data) or ICH results pointed out mutation(s) in other MMR genes (Mangold, 2007). In addition, the variant is cited as Benign/Likely Benign by reputable databases/clinical laboratories. Taking together, the variant is classified as Benign. (less)
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Likely benign
(Feb 04, 2022)
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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: SCV002505982.2
First in ClinVar: May 07, 2022 Last updated: Dec 24, 2022 |
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Benign
(Dec 06, 2021)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000888182.3
First in ClinVar: Mar 17, 2018 Last updated: Dec 31, 2022 |
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Benign
(Sep 14, 2021)
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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
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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV003838858.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
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Likely 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: SCV004015871.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
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Likely 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: SCV004024889.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
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Benign
(-)
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no assertion criteria provided
Method: clinical testing
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Lynch syndrome
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: SCV000592347.2 First in ClinVar: Jun 09, 2014 Last updated: Apr 13, 2021 |
Comment:
The MLH1 p.Gly101Gly was identified in 1 of 20 proband chromosomes (frequency: 0.05) from individuals with Muir-Torre syndrome (Mangold 2007). The variant was also identified … (more)
The MLH1 p.Gly101Gly was identified in 1 of 20 proband chromosomes (frequency: 0.05) from individuals with Muir-Torre syndrome (Mangold 2007). The variant was also identified in dbSNP (ID: rs4647220) “With other allele”, in the 1000 Genomes Project in 32 of 5000 chromosomes (frequency: 0.0064) and in the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 336 of 16482 chromosomes (frequency: 0.02) (or 329 individuals and 5 homozygous individuals) from a population of South Asian individuals, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The variant was also identified in Clinvitae database (2x), “Mismatch Repair Genes Variant Database”, InSiGHT Colon Cancer Gene Variant Database (2X), the ClinVar database (classified as a likely benign by an expert panel), and UMD (1X as an unknown variant). The p.Gly101Gly variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant occurs outside of the splicing consensus sequence, 4th base from the 5' splice region, and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing leading to the loss of a predicted splice site at a non-consensus splice site location; we cannot eliminate the possibility that an exon splice enhancer was modified and may lead to abnormal splicing or creation of a cryptic splice site however this information is not predictive enough to assume pathogenicity. Thompson et al. (2013) assessed MMR (mismatch repair) variants using multifactorial analysis, prior probabilities and likelihood ratios, as well as in vitro splicing assays and found the variant to be Class 3, uncertain significance, and having wildtype splicing. The identification of this variant in an individual with a co-occurring pathogenic variant (MSH2, c.1-?_366+?del) from our laboratory increases the likelihood this variant does not have clinical significance. In summary, based on the above information, this variant is classified as benign. (less)
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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: SCV001919882.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
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: SCV001963542.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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not provided
(Sep 19, 2013)
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no classification provided
Method: reference population
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AllHighlyPenetrant
Affected status: unknown
Allele origin:
germline
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ITMI
Accession: SCV000085535.1
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014
Comment:
Please see associated publication for description of ethnicities
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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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Structure of the human MLH1 N-terminus: implications for predisposition to Lynch syndrome. | Wu H | Acta crystallographica. Section F, Structural biology communications | 2015 | PMID: 26249686 |
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. | Richards S | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741868 |
Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing. | Bodian DL | PloS one | 2014 | PMID: 24728327 |
A multifactorial likelihood model for MMR gene variant classification incorporating probabilities based on sequence bioinformatics and tumor characteristics: a report from the Colon Cancer Family Registry. | Thompson BA | Human mutation | 2013 | PMID: 22949379 |
MSH6 mutation in Muir-Torre syndrome: could this be a rare finding? | Mangold E | The British journal of dermatology | 2007 | PMID: 17199584 |
http://www.insight-database.org/classifications/index.html?gene=MLH1&variant=c.303T%3EG | - | - | - | - |
Text-mined citations for rs4647220 ...
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.