This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 735 of the MSH2 protein (p.Ile735Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
ClinVar Genomic variation as it relates to human health
NM_000251.3(MSH2):c.2203A>C (p.Ile735Leu)
Germline
Classification
Help
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.
(1)
Help
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
1
criteria provided, single submitter
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000251.3(MSH2):c.2203A>C (p.Ile735Leu)
Variation ID: 2993411 Accession: VCV002993411.1
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p21 2: 47476564 (GRCh38) [ NCBI UCSC ] 2: 47703703 (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 Feb 29, 2024 Feb 28, 2024 Jul 8, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000251.3:c.2203A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000242.1:p.Ile735Leu missense NM_001258281.1:c.2005A>C NP_001245210.1:p.Ile669Leu missense NM_001406631.1:c.2203A>C NP_001393560.1:p.Ile735Leu missense NM_001406632.1:c.2203A>C NP_001393561.1:p.Ile735Leu missense NM_001406633.1:c.2203A>C NP_001393562.1:p.Ile735Leu missense NM_001406634.1:c.2203A>C NP_001393563.1:p.Ile735Leu missense NM_001406635.1:c.2203A>C NP_001393564.1:p.Ile735Leu missense NM_001406636.1:c.2170A>C NP_001393565.1:p.Ile724Leu missense NM_001406637.1:c.2203A>C NP_001393566.1:p.Ile735Leu missense NM_001406638.1:c.2242A>C NP_001393567.1:p.Ile748Leu missense NM_001406639.1:c.2203A>C NP_001393568.1:p.Ile735Leu missense NM_001406640.1:c.2203A>C NP_001393569.1:p.Ile735Leu missense NM_001406641.1:c.2203A>C NP_001393570.1:p.Ile735Leu missense NM_001406642.1:c.2203A>C NP_001393571.1:p.Ile735Leu missense NM_001406643.1:c.2203A>C NP_001393572.1:p.Ile735Leu missense NM_001406644.1:c.2203A>C NP_001393573.1:p.Ile735Leu missense NM_001406645.1:c.2203A>C NP_001393574.1:p.Ile735Leu missense NM_001406646.1:c.2203A>C NP_001393575.1:p.Ile735Leu missense NM_001406647.1:c.2053A>C NP_001393576.1:p.Ile685Leu missense NM_001406648.1:c.2203A>C NP_001393577.1:p.Ile735Leu missense NM_001406649.1:c.2053A>C NP_001393578.1:p.Ile685Leu missense NM_001406650.1:c.2053A>C NP_001393579.1:p.Ile685Leu missense NM_001406651.1:c.2053A>C NP_001393580.1:p.Ile685Leu missense NM_001406652.1:c.2053A>C NP_001393581.1:p.Ile685Leu missense NM_001406653.1:c.2143A>C NP_001393582.1:p.Ile715Leu missense NM_001406654.1:c.1783A>C NP_001393583.1:p.Ile595Leu missense NM_001406656.1:c.1306A>C NP_001393585.1:p.Ile436Leu missense NM_001406658.1:c.847A>C NP_001393587.1:p.Ile283Leu missense NM_001406659.1:c.847A>C NP_001393588.1:p.Ile283Leu missense NM_001406660.1:c.847A>C NP_001393589.1:p.Ile283Leu missense NM_001406661.1:c.847A>C NP_001393590.1:p.Ile283Leu missense NM_001406662.1:c.847A>C NP_001393591.1:p.Ile283Leu missense NM_001406669.1:c.847A>C NP_001393598.1:p.Ile283Leu missense NM_001406674.1:c.2203A>C NP_001393603.1:p.Ile735Leu missense NR_176230.1:n.2239A>C non-coding transcript variant NR_176231.1:n.2239A>C non-coding transcript variant NR_176232.1:n.2239A>C non-coding transcript variant NR_176233.1:n.2081A>C non-coding transcript variant NR_176234.1:n.2239A>C non-coding transcript variant NR_176235.1:n.2239A>C non-coding transcript variant NR_176236.1:n.2239A>C non-coding transcript variant NR_176237.1:n.2239A>C non-coding transcript variant NR_176238.1:n.2372A>C non-coding transcript variant NR_176239.1:n.2239A>C non-coding transcript variant NR_176241.1:n.2239A>C non-coding transcript variant NR_176242.1:n.2239A>C non-coding transcript variant NR_176243.1:n.2089A>C non-coding transcript variant NR_176244.1:n.2239A>C non-coding transcript variant NR_176245.1:n.2239A>C non-coding transcript variant NR_176246.1:n.2239A>C non-coding transcript variant NR_176247.1:n.2239A>C non-coding transcript variant NR_176248.1:n.2239A>C non-coding transcript variant NR_176249.1:n.2469A>C non-coding transcript variant NR_176250.1:n.1979A>C non-coding transcript variant NC_000002.12:g.47476564A>C NC_000002.11:g.47703703A>C NG_007110.2:g.78441A>C LRG_218:g.78441A>C LRG_218t1:c.2203A>C LRG_218p1:p.Ile735Leu - Protein change
- I595L, I715L, I283L, I669L, I724L, I735L, I436L, I685L, I748L
- Other names
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- Canonical SPDI
- NC_000002.12:47476563:A:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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| MSH2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
7404 | 7566 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Uncertain significance (1) |
criteria provided, single submitter
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Jul 8, 2023 | RCV003850506.2 |
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
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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|---|---|---|---|---|---|
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Uncertain significance
(Jul 08, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary nonpolyposis colorectal neoplasms
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004656107.1
First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 735 of the MSH2 protein (p.Ile735Leu). … (more)
This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 735 of the MSH2 protein (p.Ile735Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
|
Comment:
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. |
Comment:
This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 735 of the MSH2 protein (p.Ile735Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Massively parallel functional testing of MSH2 missense variants conferring Lynch syndrome risk. | Jia X | American journal of human genetics | 2021 | PMID: 33357406 |
Text-mined citations for this variant ...
HelpRecord last updated Sep 30, 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.