Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25759019, 31159747, 9774676, 18822302, 21120944)
ClinVar Genomic variation as it relates to human health
NM_000251.3(MSH2):c.1405C>T (p.Leu469Phe)
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.
(3)
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
3
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000251.3(MSH2):c.1405C>T (p.Leu469Phe)
Variation ID: 1771888 Accession: VCV001771888.6
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p21 2: 47463049 (GRCh38) [ NCBI UCSC ] 2: 47690188 (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 Nov 29, 2022 May 1, 2024 Nov 29, 2022 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000251.3:c.1405C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000242.1:p.Leu469Phe missense NM_001258281.1:c.1207C>T NP_001245210.1:p.Leu403Phe missense NM_001406631.1:c.1405C>T NP_001393560.1:p.Leu469Phe missense NM_001406632.1:c.1405C>T NP_001393561.1:p.Leu469Phe missense NM_001406633.1:c.1405C>T NP_001393562.1:p.Leu469Phe missense NM_001406634.1:c.1405C>T NP_001393563.1:p.Leu469Phe missense NM_001406635.1:c.1405C>T NP_001393564.1:p.Leu469Phe missense NM_001406636.1:c.1372C>T NP_001393565.1:p.Leu458Phe missense NM_001406637.1:c.1405C>T NP_001393566.1:p.Leu469Phe missense NM_001406638.1:c.1444C>T NP_001393567.1:p.Leu482Phe missense NM_001406639.1:c.1405C>T NP_001393568.1:p.Leu469Phe missense NM_001406640.1:c.1405C>T NP_001393569.1:p.Leu469Phe missense NM_001406641.1:c.1405C>T NP_001393570.1:p.Leu469Phe missense NM_001406642.1:c.1405C>T NP_001393571.1:p.Leu469Phe missense NM_001406643.1:c.1405C>T NP_001393572.1:p.Leu469Phe missense NM_001406644.1:c.1405C>T NP_001393573.1:p.Leu469Phe missense NM_001406645.1:c.1405C>T NP_001393574.1:p.Leu469Phe missense NM_001406646.1:c.1405C>T NP_001393575.1:p.Leu469Phe missense NM_001406647.1:c.1255C>T NP_001393576.1:p.Leu419Phe missense NM_001406648.1:c.1405C>T NP_001393577.1:p.Leu469Phe missense NM_001406649.1:c.1255C>T NP_001393578.1:p.Leu419Phe missense NM_001406650.1:c.1255C>T NP_001393579.1:p.Leu419Phe missense NM_001406651.1:c.1255C>T NP_001393580.1:p.Leu419Phe missense NM_001406652.1:c.1255C>T NP_001393581.1:p.Leu419Phe missense NM_001406653.1:c.1345C>T NP_001393582.1:p.Leu449Phe missense NM_001406654.1:c.985C>T NP_001393583.1:p.Leu329Phe missense NM_001406655.1:c.1405C>T NP_001393584.1:p.Leu469Phe missense NM_001406656.1:c.508C>T NP_001393585.1:p.Leu170Phe missense NM_001406657.1:c.1405C>T NP_001393586.1:p.Leu469Phe missense NM_001406658.1:c.49C>T NP_001393587.1:p.Leu17Phe missense NM_001406659.1:c.49C>T NP_001393588.1:p.Leu17Phe missense NM_001406660.1:c.49C>T NP_001393589.1:p.Leu17Phe missense NM_001406661.1:c.49C>T NP_001393590.1:p.Leu17Phe missense NM_001406662.1:c.49C>T NP_001393591.1:p.Leu17Phe missense NM_001406669.1:c.49C>T NP_001393598.1:p.Leu17Phe missense NM_001406674.1:c.1405C>T NP_001393603.1:p.Leu469Phe missense NR_176230.1:n.1441C>T NR_176231.1:n.1441C>T NR_176232.1:n.1441C>T NR_176233.1:n.1283C>T NR_176234.1:n.1441C>T NR_176235.1:n.1441C>T NR_176236.1:n.1441C>T NR_176237.1:n.1441C>T NR_176238.1:n.1441C>T NR_176239.1:n.1441C>T NR_176240.1:n.1441C>T NR_176241.1:n.1441C>T NR_176242.1:n.1441C>T NR_176243.1:n.1291C>T NR_176244.1:n.1441C>T NR_176245.1:n.1441C>T NR_176246.1:n.1441C>T NR_176247.1:n.1441C>T NR_176248.1:n.1441C>T NR_176249.1:n.1671C>T NR_176250.1:n.1181C>T NC_000002.12:g.47463049C>T NC_000002.11:g.47690188C>T NG_007110.2:g.64926C>T LRG_218:g.64926C>T LRG_218t1:c.1405C>T LRG_218p1:p.Leu469Phe - Protein change
- L17F, L482F, L329F, L469F, L170F, L403F, L419F, L449F, L458F
- Other names
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- Canonical SPDI
- NC_000002.12:47463048: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
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. |
|||
| 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
|
Jun 6, 2018 | RCV002389365.2 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Nov 29, 2022 | RCV002464661.1 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Jun 26, 2022 | RCV003095101.3 |
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
(Nov 29, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002759214.1
First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25759019, 31159747, 9774676, 18822302, 21120944) (less)
|
|
|
Uncertain significance
(Jun 26, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary nonpolyposis colorectal neoplasms
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003212860.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024 |
Comment:
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 … (more)
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. Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is not expected to disrupt MSH2 protein function. This variant has not been reported in the literature in individuals affected with MSH2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 469 of the MSH2 protein (p.Leu469Phe). (less)
|
|
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Uncertain significance
(Jun 06, 2018)
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criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002702467.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.L469F variant (also known as c.1405C>T), located in coding exon 9 of the MSH2 gene, results from a C to T substitution at nucleotide … (more)
The p.L469F variant (also known as c.1405C>T), located in coding exon 9 of the MSH2 gene, results from a C to T substitution at nucleotide position 1405. The leucine at codon 469 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. In addition, this alteration is predicted to be borderline deleteriuos by MAPP-MMR in silico analyses (Chao EC et al. Hum. Mutat. 2008 Jun;29:852-60). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
|
Comment:
Comment:
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. Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is not expected to disrupt MSH2 protein function. This variant has not been reported in the literature in individuals affected with MSH2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 469 of the MSH2 protein (p.Leu469Phe).
Comment:
The p.L469F variant (also known as c.1405C>T), located in coding exon 9 of the MSH2 gene, results from a C to T substitution at nucleotide position 1405. The leucine at codon 469 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. In addition, this alteration is predicted to be borderline deleteriuos by MAPP-MMR in silico analyses (Chao EC et al. Hum. Mutat. 2008 Jun;29:852-60). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
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:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25759019, 31159747, 9774676, 18822302, 21120944)
Comment:
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. Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is not expected to disrupt MSH2 protein function. This variant has not been reported in the literature in individuals affected with MSH2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 469 of the MSH2 protein (p.Leu469Phe).
Comment:
The p.L469F variant (also known as c.1405C>T), located in coding exon 9 of the MSH2 gene, results from a C to T substitution at nucleotide position 1405. The leucine at codon 469 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. In addition, this alteration is predicted to be borderline deleteriuos by MAPP-MMR in silico analyses (Chao EC et al. Hum. Mutat. 2008 Jun;29:852-60). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Citations for germline classification of this variant
Help| There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar. |
Text-mined citations for this variant ...
HelpRecord last updated Sep 29, 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.