ClinVar Genomic variation as it relates to human health
NM_000249.4(MLH1):c.1128T>C (p.Asp376=)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000249.4(MLH1):c.1128T>C (p.Asp376=)
Variation ID: 89643 Accession: VCV000089643.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 37025726 (GRCh38) [ NCBI UCSC ] 3: 37067217 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Mar 24, 2015 May 1, 2024 Sep 5, 2013 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000249.4:c.1128T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000240.1:p.Asp376= synonymous NM_001167617.3:c.834T>C NP_001161089.1:p.Asp278= synonymous NM_001167618.3:c.405T>C NP_001161090.1:p.Asp135= synonymous NM_001167619.3:c.405T>C NP_001161091.1:p.Asp135= synonymous NM_001258271.2:c.1128T>C NP_001245200.1:p.Asp376= synonymous NM_001258273.2:c.405T>C NP_001245202.1:p.Asp135= synonymous NM_001258274.3:c.405T>C NP_001245203.1:p.Asp135= synonymous NM_001354615.2:c.405T>C NP_001341544.1:p.Asp135= synonymous NM_001354616.2:c.405T>C NP_001341545.1:p.Asp135= synonymous NM_001354617.2:c.405T>C NP_001341546.1:p.Asp135= synonymous NM_001354618.2:c.405T>C NP_001341547.1:p.Asp135= synonymous NM_001354619.2:c.405T>C NP_001341548.1:p.Asp135= synonymous NM_001354620.2:c.834T>C NP_001341549.1:p.Asp278= synonymous NM_001354621.2:c.105T>C NP_001341550.1:p.Asp35= synonymous NM_001354622.2:c.105T>C NP_001341551.1:p.Asp35= synonymous NM_001354623.2:c.105T>C NP_001341552.1:p.Asp35= synonymous NM_001354624.2:c.54T>C NP_001341553.1:p.Asp18= synonymous NM_001354625.2:c.54T>C NP_001341554.1:p.Asp18= synonymous NM_001354626.2:c.54T>C NP_001341555.1:p.Asp18= synonymous NM_001354627.2:c.54T>C NP_001341556.1:p.Asp18= synonymous NM_001354628.2:c.1128T>C NP_001341557.1:p.Asp376= synonymous NM_001354629.2:c.1029T>C NP_001341558.1:p.Asp343= synonymous NM_001354630.2:c.1128T>C NP_001341559.1:p.Asp376= synonymous NC_000003.12:g.37025726T>C NC_000003.11:g.37067217T>C NG_007109.2:g.37377T>C LRG_216:g.37377T>C LRG_216t1:c.1128T>C LRG_216p1:p.Asp376= - Protein change
- Other names
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- Canonical SPDI
- NC_000003.12:37025725:T:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00007
Trans-Omics for Precision Medicine (TOPMed) 0.00004
The Genome Aggregation Database (gnomAD) 0.00005
Exome Aggregation Consortium (ExAC) 0.00007
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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MLH1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
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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Benign (2) |
reviewed by expert panel
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Sep 5, 2013 | RCV000075113.6 | |
Benign/Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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Mar 15, 2023 | RCV000410805.3 | |
Benign (2) |
criteria provided, multiple submitters, no conflicts
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Apr 13, 2018 | RCV000442515.2 | |
Likely benign (3) |
criteria provided, multiple submitters, no conflicts
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Aug 25, 2021 | RCV000569167.7 | |
Benign (2) |
criteria provided, single submitter
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May 23, 2018 | RCV000759078.6 | |
Benign (1) |
criteria provided, single submitter
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Jan 31, 2024 | RCV001080774.7 |
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: SCV000106105.3
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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Likely benign
(Aug 25, 2021)
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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: SCV002528623.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Likely benign
(Mar 30, 2016)
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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: SCV000684716.2
First in ClinVar: Feb 19, 2018 Last updated: Dec 11, 2022 |
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Benign
(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: SCV004018192.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.
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Benign
(Jan 31, 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: SCV000259719.10
First in ClinVar: Mar 24, 2015 Last updated: Feb 14, 2024 |
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Benign
(Jul 15, 2015)
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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: SCV000513623.4
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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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Benign
(Apr 13, 2018)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000917643.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: MLH1 c.1128T>C alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these … (more)
Variant summary: MLH1 c.1128T>C alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 1.55 fold of the estimated maximal expected allele frequency for a pathogenic variant in MLH1 causing Lynch Syndrome phenotype (0.00071), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.1128T>C has been reported in the literature in individuals affected with Lynch Syndrome, however 9 out of the reported 18 families with c.1128T>C (Asp376) also had pathogenic mutations in MLH1, MSH2 or MSH6 (Shin_2004), strongly supporting the benign nature of this variant. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. (less)
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Likely benign
(Apr 28, 2016)
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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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Counsyl
Accession: SCV000488560.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Likely benign
(Feb 19, 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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Ambry Genetics
Accession: SCV000669527.5
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely 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 23, 2018)
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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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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000888172.2
First in ClinVar: Mar 14, 2019 Last updated: Jan 01, 2022 |
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Likely Benign
(Nov 30, 2023)
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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: SCV004840959.1
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: 7
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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:
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: SCV001548738.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
MLH1, EXON 12, c.1128T>C, p.Asp376=, Heterozygous, Likely benign The MLH1 p.Asp376= variant was identified in 18 of 282 proband chromosomes (frequency: 0.06) from individuals or … (more)
MLH1, EXON 12, c.1128T>C, p.Asp376=, Heterozygous, Likely benign The MLH1 p.Asp376= variant was identified in 18 of 282 proband chromosomes (frequency: 0.06) from individuals or families with Lynch syndrome and was present in 12 of 368 control chromosomes (frequency: 0.03) from healthy individuals (Shin 2004). The variant was also identified in the following databases: dbSNP (ID: rs267607824) as "With Likely benign allele", ClinVar (3x likely benign, 3x benign including review by expert panel InSiGHT), Clinvitae, Mismatch Repair Genes Variant Database, and the Insight Hereditary Tumors Database (1x, not pathogenic). The variant was not identified in GeneInsight-COGR, Cosmic, MutDB, UMD-LSDB, or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 20 of 276984 chromosomes at a frequency of 0.00007 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include East Asian in 20 of 18854 chromosomes (freq: 0.001), while the variant was not observed in the African, Other, Latino, European, Ashkenazi Jewish, Finnish, and South Asian populations. A study by Shin 2004 found no statistically significant difference in frequency between Lynch syndrome patients and controls for this variant, and listed it as a polymorphism. The p.Asp376= 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. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. (less)
Number of individuals with the variant: 2
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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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[Clinical value of screening hereditary nonpolyposis colorectal cancer in China with protocol recommended by NCCN guidelines]. | Shen K | Zhonghua wei chang wai ke za zhi = Chinese journal of gastrointestinal surgery | 2008 | PMID: 18636350 |
Germline mutations in MLH1, MSH2 and MSH6 in Korean hereditary non-polyposis colorectal cancer families. | Shin YK | Human mutation | 2004 | PMID: 15365995 |
http://www.insight-database.org/classifications/index.html?gene=MLH1&variant=c.1128T%3EC | - | - | - | - |
Text-mined citations for rs267607824 ...
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.