ClinVar Genomic variation as it relates to human health
NM_000251.3(MSH2):c.913G>A (p.Ala305Thr)
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(2); Likely benign(8)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000251.3(MSH2):c.913G>A (p.Ala305Thr)
Variation ID: 91243 Accession: VCV000091243.38
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p21 2: 47414389 (GRCh38) [ NCBI UCSC ] 2: 47641528 (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 Dec 6, 2014 May 1, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000251.3:c.913G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000242.1:p.Ala305Thr missense NM_001258281.1:c.715G>A NP_001245210.1:p.Ala239Thr missense NC_000002.12:g.47414389G>A NC_000002.11:g.47641528G>A NG_007110.2:g.16266G>A LRG_218:g.16266G>A LRG_218t1:c.913G>A LRG_218p1:p.Ala305Thr P43246:p.Ala305Thr - Protein change
- A305T, A239T
- Other names
- p.A305T:GCA>ACA
- Canonical SPDI
- NC_000002.12:47414388: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.
Exome Aggregation Consortium (ExAC) 0.00005
The Genome Aggregation Database (gnomAD), exomes 0.00006
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
The Genome Aggregation Database (gnomAD) 0.00008
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
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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MSH2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
7352 | 7512 |
Conditions - Germline
Condition
Help
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
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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Likely benign (3) |
criteria provided, multiple submitters, no conflicts
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Dec 8, 2020 | RCV000115547.20 | |
Uncertain significance (1) |
no assertion criteria provided
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- | RCV000076748.17 | |
Uncertain significance (1) |
no assertion criteria provided
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Jun 1, 2014 | RCV000148633.11 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Jun 11, 2021 | RCV000656876.19 | |
Likely benign (1) |
criteria provided, single submitter
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Jan 31, 2024 | RCV001084038.15 | |
Likely benign (1) |
criteria provided, single submitter
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Apr 27, 2023 | RCV003492427.1 | |
MSH2-related disorder
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Likely benign (1) |
criteria provided, single submitter
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Jan 23, 2024 | RCV004542749.1 |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Aug 15, 2022 | RCV001193245.16 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely benign
(Sep 19, 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: SCV000537524.4
First in ClinVar: Sep 24, 2016 Last updated: Jun 22, 2020 |
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Uncertain significance
(Mar 05, 2020)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002071715.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
Comment:
DNA sequence analysis of the MSH2 gene demonstrated a sequence change, c.913G>A, in exon 5 that results in an amino acid change, p.Ala305Thr. This sequence … (more)
DNA sequence analysis of the MSH2 gene demonstrated a sequence change, c.913G>A, in exon 5 that results in an amino acid change, p.Ala305Thr. This sequence change has been described in the gnomAD database with a low population frequency of 0.005% (dbSNP rs63751454). The p.Ala305Thr change affects a highly conserved amino acid residue located in a domain of the MSH2 protein that is known to be functional. The p.Ala305Thr substitution appears to be possibly damaging using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). The p.Ala305Thr variant has been reported in patients with Lynch syndrome (PMIDs: 9311737, 19267393), however functional studies performed have not provided evidence that the p.Ala305Thr variant leads to aberrant MSH2 expression, cellular localization or binding, or that this variant impacts mismatch repair activity (PMID: 22102614; Arnold et al., 2009). Due to these contrasting evidences, the clinical significance of the p.Ala305Thr change remains unknown at this time. (less)
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Likely benign
(Aug 15, 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: SCV001361973.3
First in ClinVar: Jun 22, 2020 Last updated: Sep 17, 2022 |
Comment:
Variant summary: MSH2 c.913G>A (p.Ala305Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: MSH2 c.913G>A (p.Ala305Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 249030 control chromosomes, predominantly at a frequency of 0.00012 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer (6e-05 vs 0.00057), allowing no conclusion about variant significance. c.913G>A has been reported in the literature in individuals affected with colorectal cancer and/or undergoing panel-based genetic testing for Lynch syndrome/Hereditary Nonpolyposis Colorectal Cancer and in the NHLBI Exome Sequencing Project (ESP) cohort (example, Winjen_1997, Winjen_1998, Amendola_2015, Buchanan_2016, Dudley_2018, Kim_2020, Talbot_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch syndrome/Hereditary Nonpolyposis Colorectal Cancer. Several publications report experimental evidence evaluating an impact on protein function (example, Lutzen_2008, Drost_2011, Bouvet_2019, Jia_2021). The results of these studies showed no damaging effect of this variant in measures of MMR activity, no defect in nuclear localization, mismatch binding, ATP release, MSH6 binding and EXO1 binding. Nine submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. Five submitters classified the variant as likely benign, while four classified it as VUS. Based on the reproducible functional evidence as outlined above, and emerging consensus towards a benign outcome, the variant was classified as likely benign. (less)
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Likely benign
(Apr 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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Breast and/or ovarian cancer
Affected status: unknown
Allele origin:
germline
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CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV004239292.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Likely 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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Invitae
Accession: SCV000254431.12
First in ClinVar: Oct 11, 2015 Last updated: Feb 28, 2024 |
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Likely benign
(Oct 18, 2018)
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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: SCV000213040.7
First in ClinVar: Mar 24, 2015 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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Likely benign
(Jun 11, 2021)
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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: SCV000149456.14
First in ClinVar: May 17, 2014 Last updated: Jul 09, 2018 |
Comment:
This variant is associated with the following publications: (PMID: 12419761, 22949379, 25637381, 9311737, 9709044, 18383312, 22102614, 27311873, 26333163, 19267393, 11048711, 18822302, 30998989, 21120944)
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Uncertain significance
(Jul 04, 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: SCV000601493.3
First in ClinVar: Sep 28, 2017 Last updated: Jan 01, 2022 |
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Likely benign
(Dec 08, 2020)
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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: SCV002526756.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Likely benign
(Jan 23, 2024)
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criteria provided, single submitter
Method: clinical testing
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MSH2-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004785118.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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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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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001807194.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
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Uncertain significance
(Jun 01, 2014)
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no assertion criteria provided
Method: research
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Colorectal cancer, non-polyposis
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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CSER _CC_NCGL, University of Washington
Study: ESP 6500 variant annotation
Accession: SCV000190348.1 First in ClinVar: Dec 06, 2014 Last updated: Dec 06, 2014
Comment:
Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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Lynch syndrome
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001549588.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The MSH2 p.Ala305Thr variant was identified in 1 of 368 proband chromosomes (frequency: 0.003) from Dutch individuals or families with HNPCC Lynch Syndrome and was … (more)
The MSH2 p.Ala305Thr variant was identified in 1 of 368 proband chromosomes (frequency: 0.003) from Dutch individuals or families with HNPCC Lynch Syndrome and was not identified in 200 control chromosomes from healthy individuals (Wijnen 1997, Wijnen 1998). Lutzen et al (2008) used functional assays to show that the variant protein lacks any defect in mismatch binding, ATP-release, MMR activity, subcellular localization or protein-protein interactions. In an in vitro study looking at unclassified variants for possible splicing aberrations, tumours carrying the variant were found to have normal MMR activity, and lymphoblastoid cell line derived cDNA displayed normal wildtype product (Arnold 2009). An in silico model based on multivariate analysis predicted a MAPP-MMR score of 3.55, with anything >4.55 considered deleterious (Chao 2008); while an Australian study using a multifactorial likelihood model predicted the pathogenicity of the variant to be Class 3, (unclassified) (Thompson 2013). The variant was identified in dbSNP (ID: rs63751454) as “With Uncertain significance allele”, Clinvitae database (classification uncertain significance), “Mismatch Repair Genes Variant Database”, “MMR Gene Unclassified Variants Database”, InSiGHT Colon Cancer Gene Variant Database- (LOVD) (11xX as Class 3), ClinVar database (classification uncertain significance, reviewed by an expert panel, submitters InSIGHT, GeneDx, Ambry Genetics, Invitae and CSER CC NCGL: University of Washington Medical Center), and UMD (1x with ”unclassified variant” classification). This variant was also identified in the NHLBI GO Exome Sequencing Project in 1 of 8600 European American alleles (frequency: 0.0001), and in the Exome Aggregation Consortium database (August 8, 2016) in 6 of 121170 chromosomes (frequency: 0.00005) in the following populations: African in 1 of 10280 chromosomes (frequency: 0.0001) and European (Non-Finnish) in 5 of 66656 chromosomes (frequency: 0.00008), but was not seen in East Asian, European (Finnish), Latino, Other, or South Asian populations. The p.Ala305 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the 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 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. 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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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001742747.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 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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The contribution of Lynch syndrome to early onset malignancy in Ireland. | Talbot A | BMC cancer | 2021 | PMID: 34039291 |
Massively parallel functional testing of MSH2 missense variants conferring Lynch syndrome risk. | Jia X | American journal of human genetics | 2021 | PMID: 33357406 |
Performance characteristics of screening strategies to identify Lynch syndrome in women with ovarian cancer. | Kim SR | Cancer | 2020 | PMID: 32809219 |
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 |
Germline mutation prevalence in individuals with pancreatic cancer and a history of previous malignancy. | Dudley B | Cancer | 2018 | PMID: 29360161 |
Tumor testing to identify lynch syndrome in two Australian colorectal cancer cohorts. | Buchanan DD | Journal of gastroenterology and hepatology | 2017 | PMID: 27273229 |
Actionable exomic incidental findings in 6503 participants: challenges of variant classification. | Amendola LM | Genome research | 2015 | PMID: 25637381 |
A multifactorial likelihood model for MMR gene variant classification incorporating probabilities based on sequence bioinformatics and tumor characteristics: a report from the Colon Cancer Family Registry. | Thompson BA | Human mutation | 2013 | PMID: 22949379 |
A rapid and cell-free assay to test the activity of lynch syndrome-associated MSH2 and MSH6 missense variants. | Drost M | Human mutation | 2012 | PMID: 22102614 |
Classifying MLH1 and MSH2 variants using bioinformatic prediction, splicing assays, segregation, and tumor characteristics. | Arnold S | Human mutation | 2009 | PMID: 19267393 |
Functional analysis of HNPCC-related missense mutations in MSH2. | Lützen A | Mutation research | 2008 | PMID: 18822302 |
Accurate classification of MLH1/MSH2 missense variants with multivariate analysis of protein polymorphisms-mismatch repair (MAPP-MMR). | Chao EC | Human mutation | 2008 | PMID: 18383312 |
Mismatch repair genes hMLH1 and hMSH2 and colorectal cancer: a HuGE review. | Mitchell RJ | American journal of epidemiology | 2002 | PMID: 12419761 |
Clinical findings with implications for genetic testing in families with clustering of colorectal cancer. | Wijnen JT | The New England journal of medicine | 1998 | PMID: 9709044 |
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 |
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Text-mined citations for rs63751454 ...
HelpRecord last updated Jul 07, 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.