ClinVar Genomic variation as it relates to human health
NM_000251.3(MSH2):c.728G>A (p.Arg243Gln)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Uncertain significance(6); Likely benign(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000251.3(MSH2):c.728G>A (p.Arg243Gln)
Variation ID: 91189 Accession: VCV000091189.30
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p21 2: 47412496 (GRCh38) [ NCBI UCSC ] 2: 47639635 (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 Feb 6, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000251.3:c.728G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000242.1:p.Arg243Gln missense NM_001258281.1:c.530G>A NP_001245210.1:p.Arg177Gln missense NC_000002.12:g.47412496G>A NC_000002.11:g.47639635G>A NG_007110.2:g.14373G>A LRG_218:g.14373G>A LRG_218t1:c.728G>A LRG_218p1:p.Arg243Gln - Protein change
- R243Q, R177Q
- Other names
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- Canonical SPDI
- NC_000002.12:47412495: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.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
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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MSH2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
7315 | 7468 |
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 benign (2) |
criteria provided, multiple submitters, no conflicts
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Feb 23, 2023 | RCV000131412.15 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Mar 21, 2023 | RCV000411200.5 | |
Uncertain significance (5) |
criteria provided, multiple submitters, no conflicts
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Sep 1, 2021 | RCV000479306.11 | |
Likely benign (1) |
criteria provided, single submitter
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Dec 27, 2023 | RCV000524419.10 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Feb 6, 2024 | RCV000781566.5 | |
Uncertain significance (1) |
no assertion criteria provided
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- | RCV001357533.2 |
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
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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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Uncertain significance
(Aug 08, 2022)
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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: SCV000919718.3
First in ClinVar: Jun 02, 2019 Last updated: Sep 17, 2022 |
Comment:
Variant summary: MSH2 c.728G>A (p.Arg243Gln) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, connector domain of the encoded … (more)
Variant summary: MSH2 c.728G>A (p.Arg243Gln) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, connector domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251398 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.728G>A has been reported in the literature in individuals affected with hereditary nonpolyposis colorectal cancer and colorectal cancer (Auclair_2006, Zaida-Bouchaar_2017, Castillejo_2014, Moussa_2011, Bodo_2015). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. Co-occurrences with other pathogenic variants were reported in 4 patients described in the literature, including the co-occurrence of homozygous PMS2 large deletions in a patient with CMMR (MSH2 c.1413dupA, p.Pro472ThrfsX4; MSH2 c.1030C>T, p.Gln344X ; PMS2 c.2275+210_2446-1356del, p.Ala759Glyfs*8), providing supporting evidence for a benign role. Two publications report splicing evidence showing no impact on splicing by the variant (Van der Klift_2015, Auclair_2006). Additionally, another functional study based on the proportion of cells that undergo death following exposure to methylating agents reported the variant to be neutral (Bouvet_2019). 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 uncertain significance. Based on the evidence outlined above, the variant was classified as a VUS - possibly benign variant. (less)
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Uncertain significance
(Dec 22, 2015)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 1
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000488068.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Uncertain significance
(Nov 22, 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: SCV000565722.7
First in ClinVar: Apr 29, 2017 Last updated: Mar 04, 2023 |
Comment:
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in individuals with a personal or family history including colorectal … (more)
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in individuals with a personal or family history including colorectal and other cancers (Auclair 2006, Moussa 2011, Ziada-Bouchaar 2016, Mandelker 2017); Published functional studies demonstrate lack of cell survival following MNNG-induced DNA damage, suggesting neutrality (Bouvet 2019); This variant is associated with the following publications: (PMID: 16395668, 21311894, 18383312, 26247049, 27468915, 26333163, 28873162, 26116798, 24953332, 31248416, 30998989) (less)
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Likely benign
(Mar 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 1
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004018331.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic … (more)
This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. (less)
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Uncertain significance
(Sep 01, 2021)
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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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Revvity Omics, Revvity
Accession: SCV003808952.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Uncertain significance
(Feb 06, 2024)
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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: SCV004243544.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
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Likely benign
(Feb 23, 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: SCV000690126.5
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
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Uncertain significance
(Jul 20, 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: SCV002774619.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Likely benign
(Dec 27, 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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Invitae
Accession: SCV000254428.11
First in ClinVar: Oct 11, 2015 Last updated: Feb 20, 2024 |
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Likely benign
(Mar 30, 2021)
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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: SCV000186388.8
First in ClinVar: Aug 06, 2014 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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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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Malignant tumor of breast
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: SCV001553030.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The MSH2 p.Arg243Gln variant was identified in 3 of 224 proband chromosomes (frequency: 0.01) from Algerian, French and Tunisian individuals or families with Lynch syndrome … (more)
The MSH2 p.Arg243Gln variant was identified in 3 of 224 proband chromosomes (frequency: 0.01) from Algerian, French and Tunisian individuals or families with Lynch syndrome or CRC (Ziada-Bouchaar 2017, Moussa 2011, Auclair 2006). In these studies, 2 of the probands had co-occurring pathogenic MSH2 variants (c.1030C>T/ p.Gln344X and c.1413dupA/p.Pro472ThrfsX4). The variant was also identified by our laboratory in 1 individual with breast cancer, co-occurring with a pathogenic BRCA2 variant (c.7234_7235insG, p.Thr2412Serfs*2) increasing the likelihood the MSH2 c.728G>A variant may not have clinical significance. In functional studies using patient RNA analysis and minigene splicing, both assays showed normal splicing (van der Klift 2015, Auclair 2006). A bioinformatics tool, multivariate analysis of protein polymorphisms-mismatch repair (MAPP-MMR), classified the variant as neutral (Chao 2008). The variant was also identified in dbSNP (ID: rs63751455) “With Uncertain significance allele”, ClinVar (classified uncertain significance, reviewed by an expert panel (2013); submitters: INSIGHT, Invitae, Ambry Genetics, GeneDx and 3 other laboratories), and UMD-LSDB (4x classified as UV). The variant was identified in control databases in 3 of 246198 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017), observed in the following populations: Latino in 2 of 33578 chromosomes (freq: 0.00006) and European Non-Finnish in 1 of 111672 chromosomes (freq: 0.000009); it was not observed in the African, Other, Ashkenazi Jewish, East Asian, European Finnish and South Asian populations. The p.Arg243 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Gln variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (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:
germline
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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Study: VKGL Data-share Consensus
Accession: SCV001798177.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
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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:
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: SCV001958165.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 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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Massively parallel functional testing of MSH2 missense variants conferring Lynch syndrome risk. | Jia X | American journal of human genetics | 2021 | PMID: 33357406 |
Methylation Tolerance-Based Functional Assay to Assess Variants of Unknown Significance in the MLH1 and MSH2 Genes and Identify Patients With Lynch Syndrome. | Bouvet D | Gastroenterology | 2019 | PMID: 30998989 |
Prevalence of recurrent oncogenic fusion in mismatch repair-deficient colorectal carcinoma with hypermethylated MLH1 and wild-type BRAF and KRAS. | Wang J | Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc | 2019 | PMID: 30723297 |
First description of mutational analysis of MLH1, MSH2 and MSH6 in Algerian families with suspected Lynch syndrome. | Ziada-Bouchaar H | Familial cancer | 2017 | PMID: 27468915 |
Splicing analysis for exonic and intronic mismatch repair gene variants associated with Lynch syndrome confirms high concordance between minigene assays and patient RNA analyses. | van der Klift HM | Molecular genetics & genomic medicine | 2015 | PMID: 26247049 |
Diagnosis of Constitutional Mismatch Repair-Deficiency Syndrome Based on Microsatellite Instability and Lymphocyte Tolerance to Methylating Agents. | Bodo S | Gastroenterology | 2015 | PMID: 26116798 |
Development and validation of a new algorithm for the reclassification of genetic variants identified in the BRCA1 and BRCA2 genes. | Pruss D | Breast cancer research and treatment | 2014 | PMID: 25085752 |
Prevalence of germline MUTYH mutations among Lynch-like syndrome patients. | Castillejo A | European journal of cancer (Oxford, England : 1990) | 2014 | PMID: 24953332 |
Lynch syndrome in Tunisia: first description of clinical features and germline mutations. | Moussa SA | International journal of colorectal disease | 2011 | PMID: 21311894 |
Accurate classification of MLH1/MSH2 missense variants with multivariate analysis of protein polymorphisms-mismatch repair (MAPP-MMR). | Chao EC | Human mutation | 2008 | PMID: 18383312 |
Systematic mRNA analysis for the effect of MLH1 and MSH2 missense and silent mutations on aberrant splicing. | Auclair J | Human mutation | 2006 | PMID: 16395668 |
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Text-mined citations for rs63751455 ...
HelpRecord last updated May 01, 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.