The p.L743W variant (also known as c.2228T>G), located in coding exon 4 of the MSH6 gene, results from a T to G substitution at nucleotide position 2228. The leucine at codon 743 is replaced by tryptophan, an amino acid with similar properties. Based on internal structural analysis using published crystal structures, this alteration is more disruptive to the protein structure near the ATP-binding site than nearby pathogenic variants (Warren JJ et al. Mol. Cell, 2007 May;26:579-92; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
ClinVar Genomic variation as it relates to human health
NM_000179.3(MSH6):c.2228T>G (p.Leu743Trp)
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_000179.3(MSH6):c.2228T>G (p.Leu743Trp)
Variation ID: 1788028 Accession: VCV001788028.2
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p16.3 2: 47800211 (GRCh38) [ NCBI UCSC ] 2: 48027350 (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 Aug 24, 2020 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000179.3:c.2228T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000170.1:p.Leu743Trp missense NM_001281492.2:c.1838T>G NP_001268421.1:p.Leu613Trp missense NM_001281493.2:c.1322T>G NP_001268422.1:p.Leu441Trp missense NM_001281494.2:c.1322T>G NP_001268423.1:p.Leu441Trp missense NM_001406795.1:c.2324T>G NP_001393724.1:p.Leu775Trp missense NM_001406796.1:c.2228T>G NP_001393725.1:p.Leu743Trp missense NM_001406797.1:c.1931T>G NP_001393726.1:p.Leu644Trp missense NM_001406798.1:c.2228T>G NP_001393727.1:p.Leu743Trp missense NM_001406799.1:c.1703T>G NP_001393728.1:p.Leu568Trp missense NM_001406800.1:c.2228T>G NP_001393729.1:p.Leu743Trp missense NM_001406801.1:c.1931T>G NP_001393730.1:p.Leu644Trp missense NM_001406802.1:c.2324T>G NP_001393731.1:p.Leu775Trp missense NM_001406803.1:c.2228T>G NP_001393732.1:p.Leu743Trp missense NM_001406804.1:c.2150T>G NP_001393733.1:p.Leu717Trp missense NM_001406805.1:c.1931T>G NP_001393734.1:p.Leu644Trp missense NM_001406806.1:c.1703T>G NP_001393735.1:p.Leu568Trp missense NM_001406807.1:c.1703T>G NP_001393736.1:p.Leu568Trp missense NM_001406808.1:c.2228T>G NP_001393737.1:p.Leu743Trp missense NM_001406809.1:c.2228T>G NP_001393738.1:p.Leu743Trp missense NM_001406811.1:c.1322T>G NP_001393740.1:p.Leu441Trp missense NM_001406812.1:c.1322T>G NP_001393741.1:p.Leu441Trp missense NM_001406813.1:c.2234T>G NP_001393742.1:p.Leu745Trp missense NM_001406814.1:c.1322T>G NP_001393743.1:p.Leu441Trp missense NM_001406815.1:c.1322T>G NP_001393744.1:p.Leu441Trp missense NM_001406816.1:c.1322T>G NP_001393745.1:p.Leu441Trp missense NM_001406818.1:c.1931T>G NP_001393747.1:p.Leu644Trp missense NM_001406819.1:c.1931T>G NP_001393748.1:p.Leu644Trp missense NM_001406820.1:c.1931T>G NP_001393749.1:p.Leu644Trp missense NM_001406821.1:c.1931T>G NP_001393750.1:p.Leu644Trp missense NM_001406822.1:c.1931T>G NP_001393751.1:p.Leu644Trp missense NM_001406823.1:c.1322T>G NP_001393752.1:p.Leu441Trp missense NM_001406824.1:c.1931T>G NP_001393753.1:p.Leu644Trp missense NM_001406825.1:c.1931T>G NP_001393754.1:p.Leu644Trp missense NM_001406826.1:c.2060T>G NP_001393755.1:p.Leu687Trp missense NM_001406827.1:c.1931T>G NP_001393756.1:p.Leu644Trp missense NM_001406828.1:c.1931T>G NP_001393757.1:p.Leu644Trp missense NM_001406829.1:c.1322T>G NP_001393758.1:p.Leu441Trp missense NM_001406830.1:c.1931T>G NP_001393759.1:p.Leu644Trp missense NR_176256.1:n.1090T>G NR_176257.1:n.2317T>G NR_176258.1:n.2317T>G NR_176259.1:n.2317T>G NR_176261.1:n.2317T>G NC_000002.12:g.47800211T>G NC_000002.11:g.48027350T>G NG_007111.1:g.22065T>G LRG_219:g.22065T>G LRG_219t1:c.2228T>G LRG_219p1:p.Leu743Trp - Protein change
- L644W, L687W, L745W, L775W, L568W, L743W, L613W, L441W, L717W
- Other names
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- Canonical SPDI
- NC_000002.12:47800210:T: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
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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| MSH6 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
9159 | 9475 | |
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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Aug 24, 2020 | RCV002428173.2 |
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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Uncertain significance
(Aug 24, 2020)
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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: SCV002729725.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.L743W variant (also known as c.2228T>G), located in coding exon 4 of the MSH6 gene, results from a T to G substitution at nucleotide … (more)
The p.L743W variant (also known as c.2228T>G), located in coding exon 4 of the MSH6 gene, results from a T to G substitution at nucleotide position 2228. The leucine at codon 743 is replaced by tryptophan, an amino acid with similar properties. Based on internal structural analysis using published crystal structures, this alteration is more disruptive to the protein structure near the ATP-binding site than nearby pathogenic variants (Warren JJ et al. Mol. Cell, 2007 May;26:579-92; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (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:
The p.L743W variant (also known as c.2228T>G), located in coding exon 4 of the MSH6 gene, results from a T to G substitution at nucleotide position 2228. The leucine at codon 743 is replaced by tryptophan, an amino acid with similar properties. Based on internal structural analysis using published crystal structures, this alteration is more disruptive to the protein structure near the ATP-binding site than nearby pathogenic variants (Warren JJ et al. Mol. Cell, 2007 May;26:579-92; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Structure of the human MutSalpha DNA lesion recognition complex. | Warren JJ | Molecular cell | 2007 | PMID: 17531815 |
Text-mined citations for this variant ...
HelpRecord last updated May 01, 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.