ClinVar Genomic variation as it relates to human health
NM_000251.3(MSH2):c.2714C>T (p.Thr905Ile)
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(5); 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.2714C>T (p.Thr905Ile)
Variation ID: 91038 Accession: VCV000091038.36
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p21 2: 47482858 (GRCh38) [ NCBI UCSC ] 2: 47709997 (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.2714C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000242.1:p.Thr905Ile missense NM_001258281.1:c.2516C>T NP_001245210.1:p.Thr839Ile missense NC_000002.12:g.47482858C>T NC_000002.11:g.47709997C>T NG_007110.2:g.84735C>T LRG_218:g.84735C>T LRG_218t1:c.2714C>T LRG_218p1:p.Thr905Ile - Protein change
- T905I, T839I
- Other names
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- Canonical SPDI
- NC_000002.12:47482857:C:T
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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.
Trans-Omics for Precision Medicine (TOPMed) 0.00006
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 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
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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 |
7326 | 7479 |
Conditions - Germline
Condition
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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
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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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Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jan 2, 2024 | RCV000131745.18 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jun 6, 2023 | RCV000235233.17 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Feb 6, 2024 | RCV000781552.2 | |
Likely benign (1) |
criteria provided, single submitter
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Jan 29, 2024 | RCV001084144.7 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 20, 2023 | RCV003997168.2 |
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
(Jun 06, 2023)
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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: SCV000292627.14
First in ClinVar: Jul 24, 2016 Last updated: Jul 08, 2023 |
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate no damaging effect in a cell survival assay … (more)
In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate no damaging effect in a cell survival assay (Bouvet et al., 2019); Observed in an individual with colon cancer, but observed on the lost tumor allele suggesting a benign variant (Hampel et al., 2018); Observed in both cases and controls in a breast cancer case-control study (Dorling et al., 2021); This variant is associated with the following publications: (PMID: 12124176, 16995940, 25203624, 22290698, 18383312, 26333163, 20459533, 9774676, 26934580, 14526391, 18822302, 21120944, 27720647, 30998989, 33471991, 29596542) (less)
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Likely benign
(Jan 02, 2024)
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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: SCV000685070.6
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
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Likely benign
(Jan 29, 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: SCV000259987.11
First in ClinVar: Mar 24, 2015 Last updated: Feb 20, 2024 |
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Likely benign
(Mar 29, 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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Ambry Genetics
Accession: SCV000186786.9
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
(Jan 24, 2018)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000919686.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: The MSH2 c.2714C>T (p.Thr905Ile) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant … (more)
Variant summary: The MSH2 c.2714C>T (p.Thr905Ile) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). Multiple studies using computational tools predicted variant as benign (Ali_2012, Niroula_2015). This variant was found in 22/276632 control chromosomesc (gnomAD), predominantly observed in the Ashkenazi Jewish subpopulation at a frequency of 0.00148 (15/10132). This frequency is about 3 times the estimated maximal expected allele frequency of a pathogenic MSH2 variant (0.0005683), suggesting this is likely a benign polymorphism found primarily in the populations of Ashkenazi Jewish origin. This variant has not been reported in affected individuals via publications; nor has it been evaluated for functional impact via in vitro/vivo studies. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/uncertain significance. Taken together, this variant is classified as VUS-possibly benign until more evidence becomes available. (less)
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Uncertain significance
(Feb 26, 2022)
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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: SCV002534499.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The MSH2 c.2714C>T (p.T905I) variant has been reported in at least one individual with colon cancer (PMID: 29596542). However the variant was on the allele … (more)
The MSH2 c.2714C>T (p.T905I) variant has been reported in at least one individual with colon cancer (PMID: 29596542). However the variant was on the allele lost in the tumor suggesting a benign variant (PMID: 29596542). It has been reported in a large case-control study of breast cancer in 1/60466 cases and 0/53461 controls (PMID: 33471991). It was observed in 16/10350 chromosomes in the Ashkenazi Jewish subpopulation from the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org PMID: 32461654). The variant has been reported in ClinVar (Variation ID 91038). In silico tools suggest the impact of the variant on protein function is inconclusive and functional in vitro studies using methylation assays suggested that the variant is neutral. The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus the clinical significance of this variant is currently uncertain. (less)
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Likely benign
(Apr 19, 2022)
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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: SCV004220994.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 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: SCV004243573.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
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Uncertain Significance
(Nov 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004829875.1
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 missense variant replaces threonine with isoleucine at codon 905 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces threonine with isoleucine at codon 905 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A methylation tolerance assay found this variant had tolerance consistent with a neutral variant in colorectal cancer cells (PMID: 30998989), and this variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in family affected with Lynch syndrome associated cancers (PMID: 30998989). In a large breast cancer case-control study, this variant was observed in one affected individual and two healthy individuals (PMID: 33471991). This variant has been identified in 23/282122 chromosomes (16/10350 Ashkenazi Jewish chromosomes) in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 19
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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: SCV001550581.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The MSH2 p.Thr905Ile variant was identified in 1 of 930 proband chromosomes (frequency: 0.001) from individuals or families with colorectal cancer and was thought to … (more)
The MSH2 p.Thr905Ile variant was identified in 1 of 930 proband chromosomes (frequency: 0.001) from individuals or families with colorectal cancer and was thought to be a benign germline variant as it was on the allele lost in the tumour of the individual (Hampel 2018). The variant was also identified in dbSNP (ID: rs267608022) as "With Uncertain significance, other allele", in ClinVar (classified as likely benign by Ambry Genetics and Invitae; and as uncertain significance by InSiGHT, GeneDx, and Color Genomics), UMD-LSDB (identified in 1 submission). The variant was identified in control databases in 22 of 276632 chromosomes at a frequency of 0.00008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 23984 chromosomes (freq: 0.00004), Other in 1 of 6452 chromosomes (freq: 0.0002), European Non-Finnish in 5 of 126396 chromosomes (freq: 0.00004), Ashkenazi Jewish in 15 of 10132 chromosomes (freq: 0.0015); it was not observed in the Latino, East Asian, Finnish, and South Asian populations. The p.Thr905Ile residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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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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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Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
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 |
Assessment of Tumor Sequencing as a Replacement for Lynch Syndrome Screening and Current Molecular Tests for Patients With Colorectal Cancer. | Hampel H | JAMA oncology | 2018 | PMID: 29596542 |
Sanger Confirmation Is Required to Achieve Optimal Sensitivity and Specificity in Next-Generation Sequencing Panel Testing. | Mu W | The Journal of molecular diagnostics : JMD | 2016 | PMID: 27720647 |
Classification of Amino Acid Substitutions in Mismatch Repair Proteins Using PON-MMR2. | Niroula A | Human mutation | 2015 | PMID: 26333163 |
Sequencing an Ashkenazi reference panel supports population-targeted personal genomics and illuminates Jewish and European origins. | Carmi S | Nature communications | 2014 | PMID: 25203624 |
Classification of mismatch repair gene missense variants with PON-MMR. | Ali H | Human mutation | 2012 | PMID: 22290698 |
Accurate classification of MLH1/MSH2 missense variants with multivariate analysis of protein polymorphisms-mismatch repair (MAPP-MMR). | Chao EC | Human mutation | 2008 | PMID: 18383312 |
Text-mined citations for rs267608022 ...
HelpRecord last updated May 08, 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.