ClinVar Genomic variation as it relates to human health
NM_000251.3(MSH2):c.942+3A>G
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.
Likely pathogenic(5); Uncertain significance(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000251.3(MSH2):c.942+3A>G
Variation ID: 418625 Accession: VCV000418625.26
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p21 2: 47641560 (GRCh37) [ NCBI UCSC ] 2: 47414421 (GRCh38) [ 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 Apr 29, 2017 Feb 20, 2024 Jan 21, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000251.3:c.942+3A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001258281.1:c.744+3A>G intron variant NC_000002.12:g.47414421A>G NC_000002.11:g.47641560A>G NG_007110.2:g.16298A>G LRG_218:g.16298A>G LRG_218t1:c.942+3A>G - Protein change
- Other names
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- Canonical SPDI
- NC_000002.12:47414420:A:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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MSH2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
7262 | 7411 |
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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Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jan 24, 2023 | RCV000479341.10 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 21, 2024 | RCV000530947.9 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Apr 27, 2023 | RCV001019334.10 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Sep 27, 2023 | RCV003387853.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Oct 12, 2023 | RCV003463979.1 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Jan 24, 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: SCV000565825.5
First in ClinVar: Apr 29, 2017 Last updated: Nov 11, 2023 |
Comment:
Published functional studies demonstrate a damaging effect: RNA studies demonstrate abnormal splicing (Karam et al., 2019); Not observed at significant frequency in large population cohorts … (more)
Published functional studies demonstrate a damaging effect: RNA studies demonstrate abnormal splicing (Karam et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 33003368, 31642931) (less)
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Uncertain significance
(Nov 29, 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: SCV001134379.3
First in ClinVar: Jan 05, 2020 Last updated: Jan 06, 2024 |
Comment:
It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported to result in aberrant splicing … (more)
It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported to result in aberrant splicing (PMID: 31642931 (2019)). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper MSH2 mRNA splicing . Based on the available information, we are unable to determine the clinical significance of this variant. (less)
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Likely pathogenic
(Jan 21, 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: SCV000625483.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change falls in intron 5 of the MSH2 gene. It does not directly change the encoded amino acid sequence of the MSH2 protein. … (more)
This sequence change falls in intron 5 of the MSH2 gene. It does not directly change the encoded amino acid sequence of the MSH2 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of MSH2-related conditions (PMID: 31642931). ClinVar contains an entry for this variant (Variation ID: 418625). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 5, but is expected to preserve the integrity of the reading-frame (Invitae). This variant disrupts the c.942+3 nucleotide in the MSH2 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 8062247, 10978353, 15222003, 16395668, 19419416, 20682701, 21681552, 22883484, 24310308). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
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Likely pathogenic
(Apr 27, 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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Ambry Genetics
Accession: SCV001180678.4
First in ClinVar: Mar 16, 2020 Last updated: Jul 08, 2023 |
Comment:
The c.942+3A>G intronic variant results from an A to G substitution 3 nucleotides after coding exon 5 in the MSH2 gene. This alteration was identified … (more)
The c.942+3A>G intronic variant results from an A to G substitution 3 nucleotides after coding exon 5 in the MSH2 gene. This alteration was identified in an individual whose endometrial tumor demonstrated loss of both MSH2/MSH6 on immunohistochemistry (IHC) and had a family history of Lynch-associated cancers (Ambry internal data). While this exact alteration has not been reported in the literature, an alteration at the same nucleotide position (c.942+3A>T) has been reported in numerous individuals meeting clinical diagnostic criteria for Lynch syndrome and has been shown by multiple functional studies to cause exon 5 skipping (South CD et al. J. Natl. Cancer Inst. 2008 Feb;100(4):277-81; Desai DC et al. J. Med. Genet. 2000 Sep;37(9):646-52; Arnold S et al. Hum. Mutat. 2009 May;30(5):757-70; Auclair J et al. Hum. Mutat. 2006 Feb;27(2):145-54; Casey G et al. JAMA. 2005 Feb;293(7):799-809; Chong G et al. Hum. Mutat. 2009 Aug;30(8):E797-812). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature, 2016 08;536:285-91). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Likely pathogenic
(Sep 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary nonpolyposis colon cancer
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004100206.1
First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023 |
Comment:
Variant summary: MSH2 c.942+3A>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly … (more)
Variant summary: MSH2 c.942+3A>G 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 canonical 5' splicing donor site. One predict the variant weakens a canonical 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing and re-classified this variant from VUS to likely pathogenic (example: Karam_2019). The variant was absent in 30582 control chromosomes (gnomAD). c.942+3A>G has been reported in the literature in individuals that had targeted multi-gene panel testing for hereditary cancer (example: Karam_2019 and Bhai_2021). The following publications have been ascertained in the context of this evaluation (PMID: 31642931, 34326862). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=3) and likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Likely pathogenic
(Oct 12, 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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Baylor Genetics
Accession: SCV004196192.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Uncertain significance
(Nov 09, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV001351193.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This variant causes an A>G nucleotide substitution at the +3 position of intron 5 of the MSH2 gene. Splice site prediction tools are inconclusive regarding … (more)
This variant causes an A>G nucleotide substitution at the +3 position of intron 5 of the MSH2 gene. Splice site prediction tools are inconclusive regarding the impact of this variant on RNA splicing. RNA studies have been reported that state this variant results in abnormal splicing of mRNA, however, the specific consequences and their quantitation are not known (ClinVar variation ID: 418625). This variant has been reported in an individual affected with endometrial cancer that demonstrated loss of both MSH2 and MSH6 proteins via immunohistochemistry analysis, and who had a family history of Lynch syndrome associated cancer (communication with an external laboratory; ClinVar SCV001180678.2). Other variants at this +3 position are described to be disease-causing (ClinVar Variation ID: 36580, 1200813). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, additional functional and clinical studies are necessary to determine the role of this variant in disease conclusively. Therefore, 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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Analysis of Sequence and Copy Number Variants in Canadian Patient Cohort With Familial Cancer Syndromes Using a Unique Next Generation Sequencing Based Approach. | Bhai P | Frontiers in genetics | 2021 | PMID: 34326862 |
Assessment of Diagnostic Outcomes of RNA Genetic Testing for Hereditary Cancer. | Karam R | JAMA network open | 2019 | PMID: 31642931 |
ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis). | Hegde M | Genetics in medicine : official journal of the American College of Medical Genetics | 2014 | PMID: 24310308 |
Patients with Lynch syndrome mismatch repair gene mutations are at higher risk for not only upper tract urothelial cancer but also bladder cancer. | Skeldon SC | European urology | 2013 | PMID: 22883484 |
Characterization of germline mutations of MLH1 and MSH2 in unrelated south American suspected Lynch syndrome individuals. | Valentin MD | Familial cancer | 2011 | PMID: 21681552 |
The genetic basis of colorectal cancer in a population-based incident cohort with a high rate of familial disease. | Woods MO | Gut | 2010 | PMID: 20682701 |
Germ line MLH1 and MSH2 mutations in Taiwanese Lynch syndrome families: characterization of a founder genomic mutation in the MLH1 gene. | Tang R | Clinical genetics | 2009 | PMID: 19419416 |
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 |
Systematic mRNA analysis for the effect of MLH1 and MSH2 missense and silent mutations on aberrant splicing. | Auclair J | Human mutation | 2006 | PMID: 16395668 |
Association of colonic and endometrial carcinomas in Portuguese families with hereditary nonpolyposis colorectal carcinoma significantly increases the probability of detecting a pathogenic mutation in mismatch repair genes, primarily the MSH2 gene. | Lage PA | Cancer | 2004 | PMID: 15222003 |
Recurrent germline mutation in MSH2 arises frequently de novo. | Desai DC | Journal of medical genetics | 2000 | PMID: 10978353 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
hMSH2 mutations in hereditary nonpolyposis colorectal cancer kindreds. | Liu B | Cancer research | 1994 | PMID: 8062247 |
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Text-mined citations for rs193922376 ...
HelpRecord last updated Feb 28, 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.