ClinVar Genomic variation as it relates to human health
NM_000249.4(MLH1):c.304G>A (p.Glu102Lys)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000249.4(MLH1):c.304G>A (p.Glu102Lys)
Variation ID: 90141 Accession: VCV000090141.25
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 37001051 (GRCh38) [ NCBI UCSC ] 3: 37042542 (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 May 29, 2016 Sep 16, 2024 Jun 13, 2018 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- E102K
- Other names
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- Canonical SPDI
- NC_000003.12:37001050: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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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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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
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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 pathogenic (1) |
reviewed by expert panel
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Jun 13, 2018 | RCV000075627.4 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 27, 2020 | RCV000216042.5 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Feb 20, 2024 | RCV000493419.4 | |
Uncertain significance (1) |
no assertion criteria provided
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- | RCV000501856.7 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Feb 15, 2021 | RCV000781538.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Oct 10, 2022 | RCV000807476.5 | |
Likely pathogenic (1) |
no assertion criteria provided
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- | RCV001353830.1 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Sep 26, 2023 | RCV003451127.2 |
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
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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
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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 pathogenic
(Jun 13, 2018)
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reviewed by expert panel
Method: curation
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Lynch syndrome 1
Affected status: yes
Allele origin:
germline
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International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
Accession: SCV000106629.4
First in ClinVar: Dec 19, 2013 Last updated: Dec 11, 2022 |
Comment:
Multifactorial likelihood analysis posterior probability > 0.99 (0.995)
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Likely pathogenic
(Feb 15, 2019)
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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: SCV001134310.3
First in ClinVar: Jan 05, 2020 Last updated: Jan 01, 2022 |
Comment:
Not found in the total gnomAD dataset, and the data is high quality (0/251334 chr). Statistically enriched in patients compared to ethnically matched controls. Found … (more)
Not found in the total gnomAD dataset, and the data is high quality (0/251334 chr). Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Located in potentially important domain of the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. Results on protein functions were inconclusive. (less)
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Likely pathogenic
(Sep 26, 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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Baylor Genetics
Accession: SCV004195098.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Likely pathogenic
(Aug 09, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV001340144.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
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Likely pathogenic
(Feb 20, 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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GeneDx
Accession: SCV000581719.5
First in ClinVar: Jul 02, 2017 Last updated: Sep 16, 2024 |
Comment:
Functional studies support a damaging effect: most show reduced mismatch repair activity and decreased expression levels (PMID: 11555625, 17510385, 23403630); Observed in patients with Lynch-related … (more)
Functional studies support a damaging effect: most show reduced mismatch repair activity and decreased expression levels (PMID: 11555625, 17510385, 23403630); Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (PMID: 12183410, 18383312, 21642682); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22736432, 18383312, 16395668, 23403630, 11555625, 21642682, 25525159, 16995940, 17510385, 26096739, 23554159, 23741719, 11781295, 14526391, 31857677, 33303966, 22753075, 16083711, 21120944, 11948175, 16341550, 18373977, 34326862, 12183410) (less)
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Likely pathogenic
(Feb 15, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hereditary nonpolyposis colon cancer
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000919653.2
First in ClinVar: Jun 02, 2019 Last updated: Jun 22, 2020 |
Comment:
Variant summary: MLH1 c.304G>A (p.Glu102Lys) results in a conservative amino acid change located in the N-terminal DNA mismatch repair protein family domain (IPR002099) of the … (more)
Variant summary: MLH1 c.304G>A (p.Glu102Lys) results in a conservative amino acid change located in the N-terminal DNA mismatch repair protein family domain (IPR002099) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. The presence of a cryptic 5' donor site 5 bp upstream of the canonical splice site was however noted at exon 3. Nakagawa et al (2002) suggest that this cryptic splice site is preferentially/exclusively used when the variant is present, resulting in a deletion of the last 5 bp of exon 3, eventually causing a downstream frameshift. A different study however, was unable to detect such an effect and reported no aberrant splicing in relation to the variant (Auclair_2006). Additional functional studies show defective or partially defective MMR activity (Ellison_2001; Hinrichsen_2013; Takahashi_2007, Reyes_2020). The variant was absent in 251344 control chromosomes (gnomAD) but has been reported in the literature in individuals affected with Lynch Syndrome (e.g. Duraturo_2015, Nakagawa_2002). Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1) and likely pathogenic (n=5, including one expert panel- International Society for Gastrointestinal Hereditary Tumours (InSiGHT)). Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Pathogenic
(Jul 12, 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: SCV004186386.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
This variant is considered pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 12183410, 16341550].
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Likely pathogenic
(Oct 10, 2022)
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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: SCV000947529.5
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 90141). This missense change has been observed in individuals with Lynch syndrome (PMID: 12183410, 21642682, 22736432, … (more)
ClinVar contains an entry for this variant (Variation ID: 90141). This missense change has been observed in individuals with Lynch syndrome (PMID: 12183410, 21642682, 22736432, 23729658, 28514183, 31857677). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 102 of the MLH1 protein (p.Glu102Lys). An algorithm developed specifically for the MLH1 gene suggests that this missense change is likely to be deleterious (PMID: 18383312). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects MLH1 function (PMID: 11555625, 17510385, 18373977, 23403630). (less)
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Likely pathogenic
(Nov 27, 2020)
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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: SCV000276633.7
First in ClinVar: May 29, 2016 Last updated: May 01, 2024 |
Comment:
The p.E102K variant (also known as c.304G>A), located in coding exon 3 of the MLH1 gene, results from a G to A substitution at nucleotide … (more)
The p.E102K variant (also known as c.304G>A), located in coding exon 3 of the MLH1 gene, results from a G to A substitution at nucleotide position 304. The glutamic acid at codon 102 is replaced by lysine, an amino acid with similar properties. This variant has been reported in an HNPCC family which met Amsterdam criteria and in vitro studies have found that the c.304G>A nucleotide substitution results in a 5-bp deletion in the 3' end of exon 3 (Nakagawa H et al. Cancer Res. 2002 Aug 15;62(16):4579-82). Additionally, further functional studies have shown decreased or complete loss of MMR function (Ellison AR. et al. Hum. Mol. Genet. 2001:1889-900; Hinrichsen I et al. Clin. Cancer Res. 2013 May; 19(9):2432-41). However, Takahashi et al. also studied the MMR activity of this variant in vitro and found this variant to result in an MMR function of 44.4% compared to 79.7% in WT which they report as inconclusive (Takahashi M et al. Cancer Research. 2007: 4595-60). Based on protein sequence alignment, this amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
unknown
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000691845.1
First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018 |
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Likely pathogenic
(-)
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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: SCV000592348.2 First in ClinVar: Aug 28, 2017 Last updated: Apr 13, 2021 |
Comment:
Note: This variant was identified by this lab in a Teresa Minella. IHC not interpretable and MSI results were high.
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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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Identification of MLH2/hPMS1 dominant mutations that prevent DNA mismatch repair function. | Reyes GX | Communications biology | 2020 | PMID: 33303966 |
Retained mismatch repair protein expression occurs in approximately 6% of microsatellite instability-high cancers and is associated with missense mutations in mismatch repair genes. | Hechtman JF | Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc | 2020 | PMID: 31857677 |
Multigene Panel Testing Provides a New Perspective on Lynch Syndrome. | Espenschied CR | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2017 | PMID: 28514183 |
Multivariate analysis as a method for evaluating the pathogenicity of novel genetic MLH1 variants in patients with colorectal cancer and microsatellite instability. | Duraturo F | International journal of molecular medicine | 2015 | PMID: 26096739 |
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. | Xiong HY | Science (New York, N.Y.) | 2015 | PMID: 25525159 |
UMD-MLH1/MSH2/MSH6 databases: description and analysis of genetic variations in French Lynch syndrome families. | Grandval P | Database : the journal of biological databases and curation | 2013 | PMID: 23729658 |
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 |
Comprehensive functional assessment of MLH1 variants of unknown significance. | Borràs E | Human mutation | 2012 | PMID: 22736432 |
Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. | Bonadona V | JAMA | 2011 | PMID: 21642682 |
Accurate classification of MLH1/MSH2 missense variants with multivariate analysis of protein polymorphisms-mismatch repair (MAPP-MMR). | Chao EC | Human mutation | 2008 | PMID: 18383312 |
The interplay between hMLH1 and hMRE11: role in MMR and the effect of hMLH1 mutations. | Zhao N | Biochemical and biophysical research communications | 2008 | PMID: 18373977 |
Functional analysis of human MLH1 variants using yeast and in vitro mismatch repair assays. | Takahashi M | Cancer research | 2007 | PMID: 17510385 |
In silico and in vivo splicing analysis of MLH1 and MSH2 missense mutations shows exon- and tissue-specific effects. | Lastella P | BMC genomics | 2006 | PMID: 16995940 |
Systematic mRNA analysis for the effect of MLH1 and MSH2 missense and silent mutations on aberrant splicing. | Auclair J | Human mutation | 2006 | PMID: 16395668 |
Aberrant splicing in MLH1 and MSH2 due to exonic and intronic variants. | Pagenstecher C | Human genetics | 2006 | PMID: 16341550 |
Missense mutations in hMLH1 and hMSH2 are associated with exonic splicing enhancers. | Gorlov IP | American journal of human genetics | 2003 | PMID: 14526391 |
Allele separation facilitates interpretation of potential splicing alterations and genomic rearrangements. | Nakagawa H | Cancer research | 2002 | PMID: 12183410 |
Mutations within the hMLH1 and hPMS2 subunits of the human MutLalpha mismatch repair factor affect its ATPase activity, but not its ability to interact with hMutSalpha. | Räschle M | The Journal of biological chemistry | 2002 | PMID: 11948175 |
Functional analysis of hMLH1 variants and HNPCC-related mutations using a human expression system. | Trojan J | Gastroenterology | 2002 | PMID: 11781295 |
Functional analysis of human MLH1 and MSH2 missense variants and hybrid human-yeast MLH1 proteins in Saccharomyces cerevisiae. | Ellison AR | Human molecular genetics | 2001 | PMID: 11555625 |
http://www.insight-database.org/classifications/?gene=MLH1&variant=c.304G%3EA | - | - | - | - |
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Text-mined citations for rs63750453 ...
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.