ClinVar Genomic variation as it relates to human health
NM_000249.4(MLH1):c.1896G>A (p.Glu632=)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000249.4(MLH1):c.1896G>A (p.Glu632=)
Variation ID: 89930 Accession: VCV000089930.26
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 37047683 (GRCh38) [ NCBI UCSC ] 3: 37089174 (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 Oct 13, 2024 Sep 5, 2013 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000249.4:c.1896G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000240.1:p.Glu632= synonymous NM_001167617.3:c.1602G>A NP_001161089.1:p.Glu534= synonymous NM_001167618.3:c.1173G>A NP_001161090.1:p.Glu391= synonymous NM_001167619.3:c.1173G>A NP_001161091.1:p.Glu391= synonymous NM_001258271.2:c.1896G>A NP_001245200.1:p.Glu632= synonymous NM_001258273.2:c.1173G>A NP_001245202.1:p.Glu391= synonymous NM_001258274.3:c.1173G>A NP_001245203.1:p.Glu391= synonymous NM_001354615.2:c.1173G>A NP_001341544.1:p.Glu391= synonymous NM_001354616.2:c.1173G>A NP_001341545.1:p.Glu391= synonymous NM_001354617.2:c.1173G>A NP_001341546.1:p.Glu391= synonymous NM_001354618.2:c.1173G>A NP_001341547.1:p.Glu391= synonymous NM_001354619.2:c.1173G>A NP_001341548.1:p.Glu391= synonymous NM_001354620.2:c.1602G>A NP_001341549.1:p.Glu534= synonymous NM_001354621.2:c.873G>A NP_001341550.1:p.Glu291= synonymous NM_001354622.2:c.873G>A NP_001341551.1:p.Glu291= synonymous NM_001354623.2:c.873G>A NP_001341552.1:p.Glu291= synonymous NM_001354624.2:c.822G>A NP_001341553.1:p.Glu274= synonymous NM_001354625.2:c.822G>A NP_001341554.1:p.Glu274= synonymous NM_001354626.2:c.822G>A NP_001341555.1:p.Glu274= synonymous NM_001354627.2:c.822G>A NP_001341556.1:p.Glu274= synonymous NM_001354628.2:c.1896G>A NP_001341557.1:p.Glu632= synonymous NM_001354629.2:c.1797G>A NP_001341558.1:p.Glu599= synonymous NM_001354630.2:c.1732-834G>A intron variant NC_000003.12:g.37047683G>A NC_000003.11:g.37089174G>A NG_007109.2:g.59334G>A LRG_216:g.59334G>A LRG_216t1:c.1896G>A LRG_216p1:p.Glu632= - Protein change
- Other names
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- Canonical SPDI
- NC_000003.12:37047682: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
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
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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Pathogenic (2) |
reviewed by expert panel
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Sep 5, 2013 | RCV000075409.6 | |
Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Jun 2, 2021 | RCV000498248.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 18, 2023 | RCV000524256.6 | |
Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Apr 23, 2024 | RCV000605751.3 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 1, 2023 | RCV001013527.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 30, 2019 | RCV001193961.1 |
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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Pathogenic
(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: SCV000106404.3
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:
Variant causes splicing aberration interrupting functional domain: full inactivation of variant allele
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Pathogenic
(Sep 30, 2019)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001363157.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: MLH1 c.1896G>A (p.Glu632Glu) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a … (more)
Variant summary: MLH1 c.1896G>A (p.Glu632Glu) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site. One predict the variant weakens a 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Wijnen_1996). The variant was absent in 251398 control chromosomes. c.1896G>A has been reported in the literature in multiple individuals affected with Lynch Syndrome and colorectal cancer (Wijnen_1996, Wagner_2002, Ramsoekh_2008, vanLier_2012, DeLellis_2013, tenBroeke_2018). These data indicate that the variant is very likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jun 02, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000889390.2
First in ClinVar: Mar 13, 2019 Last updated: Jan 03, 2022 |
Comment:
The variant is located at the last nucleotide of exon 16 and has been reported to result in aberrant RNA splicing in vitro (PMIDs: 8571956 … (more)
The variant is located at the last nucleotide of exon 16 and has been reported to result in aberrant RNA splicing in vitro (PMIDs: 8571956 (1996)). This variant has been reported in multiple individuals/ families affected with Lynch syndrome or colorectal cancer in the published literature (PMIDs: 8571956 (1996), 12414824 (2002), 18625694 (2008), 22081473 (2012), 24278394 (2013)). In addition, loss of MLH1 and PMS2 expression by tumor immunohistochemistry (IHC) has been reported in tumor specimens from individuals carrying this variant (PMIDs: 22081473 (2012) and 29758216 (2018)). Therefore, the variant is classified as pathogenic. (less)
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Likely pathogenic
(Jul 24, 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: SCV004187357.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 8571956]. This variant has been reported in multiple individuals with … (more)
This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 8571956]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 8571956]. (less)
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Pathogenic
(Jan 08, 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: SCV004843232.1
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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Comment:
This synonymous variant does not change the amino acid sequence of the MLH1 protein. However, this variant causes a G to A nucleotide substitution at … (more)
This synonymous variant does not change the amino acid sequence of the MLH1 protein. However, this variant causes a G to A nucleotide substitution at the last nucleotide of exon 16 of the MLH1 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. A functional RNA study has shown that this variant causes skipping of exon 16 in the RNA transcript and results in truncation of the protein product (PMID: 8571956). This variant has been reported in at least 5 individuals from two families that have a total of ten individuals with colon cancer (PMID: 8571956, 12414824). This variant has been reported in additional individuals affected with colorectal cancer and endometrial cancer (PMID: 18625694, 22081473, Color internal data). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
Number of individuals with the variant: 1
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Pathogenic
(Jul 18, 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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Ambry Genetics
Accession: SCV001174125.4
First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024 |
Comment:
The c.1896G>A pathogenic mutation (also known as p.E632E), located in coding exon 16 of the MLH1 gene. This variant results from a G to A … (more)
The c.1896G>A pathogenic mutation (also known as p.E632E), located in coding exon 16 of the MLH1 gene. This variant results from a G to A substitution at nucleotide position 1896. This nucleotide substitution does not change the glutamic acid at codon 632. However, this change occurs in the last base pair of coding exon 16, which makes it likely to have some effect on normal mRNA splicing. This mutation has been identified in multiple, unrelated HNPCC/Lynch syndrome families (Wijnen J et al. Am J Hum Genet. 1996 Feb;58(2):300-7; Wijnen J et al. Am J Hum Genet. 1997 Aug;61(2):329-35; Wagner A et al. J Med Genet. 2002 Nov;39(11):833-7; Ramsoekh D et al. Gut. 2008 Nov;57(11):1539-44; van Lier MG et al. J Pathol. 2012 Apr;226(5):764-74; De Lellis L et al. PLoS One. 2013 Nov 20;8(11):e81194; Ambry internal data). In addition, this variant has been identified in probands whose Lynch syndrome-associated tumor demonstrated high microsatellite instability and loss of MLH1 and PMS2 expression by immunohistochemistry (van Lier MG et al. J Pathol. 2012 Apr;226(5):764-74; Ambry internal data). In one report, RT-PCR and protein truncation studies indicated that this alteration led to aberrant splicing resulting in skipping of exon 16 (Wijnen J et al. Am J Hum Genet. 1996 Feb;58(2):300-7). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Likely pathogenic
(Apr 23, 2024)
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criteria provided, single submitter
Method: clinical testing
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Colorectal cancer, hereditary nonpolyposis, type 2
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV005368096.1
First in ClinVar: Oct 13, 2024 Last updated: Oct 13, 2024 |
Comment:
Criteria applied: PS3,PM2_SUP,PP4
Clinical Features:
Breast carcinoma (present)
Sex: female
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Pathogenic
(Sep 04, 2019)
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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: SCV000589590.6
First in ClinVar: Aug 20, 2017 Last updated: Mar 04, 2023 |
Comment:
Exonic splice site variant resulting in the production of full-length transcript as well as a transcript with an in-frame deletion of exon 16 (Wijnen 1996); … (more)
Exonic splice site variant resulting in the production of full-length transcript as well as a transcript with an in-frame deletion of exon 16 (Wijnen 1996); Not observed in large population cohorts (Lek 2016); In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 12414824, 12373605, 22081473, 24278394, 25525159, 18625694, 9311737, 8571956) (less)
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Pathogenic
(Sep 18, 2023)
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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: SCV000260588.7
First in ClinVar: Mar 24, 2015 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing … (more)
For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing resulting in unknown protein product impact (PMID: 8571956; Invitae). ClinVar contains an entry for this variant (Variation ID: 89930). This variant has been observed in individual(s) with Lynch syndrome (PMID: 8571956, 12414824, 18625694). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects codon 632 of the MLH1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MLH1 protein. This variant also falls at the last nucleotide of exon 16, which is part of the consensus splice site for this exon. (less)
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Pathogenic
(Nov 01, 2023)
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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: SCV001345310.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This synonymous variant does not change the amino acid sequence of the MLH1 protein. However, this variant causes a G to A nucleotide substitution at … (more)
This synonymous variant does not change the amino acid sequence of the MLH1 protein. However, this variant causes a G to A nucleotide substitution at the last nucleotide of exon 16 of the MLH1 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. A functional RNA study has shown that this variant causes skipping of exon 16 in the RNA transcript and results in truncation of the protein product (PMID: 8571956). This variant has been reported in at least 5 affected individuals from two families that have a total of ten individuals with colon cancer (PMID: 8571956, 12414824). This variant has been reported in additional individuals affected with colorectal cancer and endometrial cancer (PMID: 18625694, 22081473). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
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Uncertain significance
(-)
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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: SCV001548765.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
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Pathogenic
(-)
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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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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: SCV001956311.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Colorectal cancer, hereditary nonpolyposis, type 2
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: SCV000734271.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
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Pathogenic
(-)
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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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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001927939.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Pathogenic
(-)
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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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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: SCV001968007.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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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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Molecular Background of Colorectal Tumors From Patients With Lynch Syndrome Associated With Germline Variants in PMS2. | Ten Broeke SW | Gastroenterology | 2018 | PMID: 29758216 |
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 |
Integrative analysis of hereditary nonpolyposis colorectal cancer: the contribution of allele-specific expression and other assays to diagnostic algorithms. | De Lellis L | PloS one | 2013 | PMID: 24278394 |
Yield of routine molecular analyses in colorectal cancer patients ≤70 years to detect underlying Lynch syndrome. | van Lier MG | The Journal of pathology | 2012 | PMID: 22081473 |
A high incidence of MSH6 mutations in Amsterdam criteria II-negative families tested in a diagnostic setting. | Ramsoekh D | Gut | 2008 | PMID: 18625694 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Genetic testing in hereditary non-polyposis colorectal cancer families with a MSH2, MLH1, or MSH6 mutation. | Wagner A | Journal of medical genetics | 2002 | PMID: 12414824 |
Genomic deletions of MSH2 and MLH1 in colorectal cancer families detected by a novel mutation detection approach. | Gille JJ | British journal of cancer | 2002 | PMID: 12373605 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Hereditary nonpolyposis colorectal cancer families not complying with the Amsterdam criteria show extremely low frequency of mismatch-repair-gene mutations. | Wijnen J | American journal of human genetics | 1997 | PMID: 9311737 |
Majority of hMLH1 mutations responsible for hereditary nonpolyposis colorectal cancer cluster at the exonic region 15-16. | Wijnen J | American journal of human genetics | 1996 | PMID: 8571956 |
http://www.insight-database.org/classifications/index.html?gene=MLH1&variant=c.1896G%3EA | - | - | - | - |
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Text-mined citations for rs63751632 ...
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.