This missense variant replaces histidine with tyrosine at codon 164 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MSH6-related disorders in the literature. This variant has been identified in 1/246186 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.
ClinVar Genomic variation as it relates to human health
NM_000179.3(MSH6):c.490C>T (p.His164Tyr)
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.
(4)
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
4
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000179.3(MSH6):c.490C>T (p.His164Tyr)
Variation ID: 1744033 Accession: VCV001744033.5
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p16.3 2: 47795926 (GRCh38) [ NCBI UCSC ] 2: 48023065 (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 Jun 16, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000179.3:c.490C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000170.1:p.His164Tyr missense NM_001281492.2:c.238-2685C>T intron variant NM_001281493.2:c.-279-2685C>T intron variant NM_001281494.2:c.-413C>T 5 prime UTR NM_001406795.1:c.586C>T NP_001393724.1:p.His196Tyr missense NM_001406796.1:c.490C>T NP_001393725.1:p.His164Tyr missense NM_001406797.1:c.193C>T NP_001393726.1:p.His65Tyr missense NM_001406798.1:c.490C>T NP_001393727.1:p.His164Tyr missense NM_001406799.1:c.-36C>T NM_001406800.1:c.490C>T NP_001393729.1:p.His164Tyr missense NM_001406801.1:c.193C>T NP_001393730.1:p.His65Tyr missense NM_001406802.1:c.586C>T NP_001393731.1:p.His196Tyr missense NM_001406803.1:c.490C>T NP_001393732.1:p.His164Tyr missense NM_001406804.1:c.412C>T NP_001393733.1:p.His138Tyr missense NM_001406805.1:c.193C>T NP_001393734.1:p.His65Tyr missense NM_001406806.1:c.-36C>T NM_001406807.1:c.-36C>T NM_001406808.1:c.490C>T NP_001393737.1:p.His164Tyr missense NM_001406809.1:c.490C>T NP_001393738.1:p.His164Tyr missense NM_001406813.1:c.496C>T NP_001393742.1:p.His166Tyr missense NM_001406814.1:c.-505C>T NM_001406817.1:c.490C>T NP_001393746.1:p.His164Tyr missense NM_001406818.1:c.193C>T NP_001393747.1:p.His65Tyr missense NM_001406819.1:c.193C>T NP_001393748.1:p.His65Tyr missense NM_001406820.1:c.193C>T NP_001393749.1:p.His65Tyr missense NM_001406821.1:c.193C>T NP_001393750.1:p.His65Tyr missense NM_001406822.1:c.193C>T NP_001393751.1:p.His65Tyr missense NM_001406824.1:c.193C>T NP_001393753.1:p.His65Tyr missense NM_001406825.1:c.193C>T NP_001393754.1:p.His65Tyr missense NM_001406826.1:c.322C>T NP_001393755.1:p.His108Tyr missense NM_001406827.1:c.193C>T NP_001393756.1:p.His65Tyr missense NM_001406828.1:c.193C>T NP_001393757.1:p.His65Tyr missense NM_001406830.1:c.193C>T NP_001393759.1:p.His65Tyr missense NM_001407362.1:c.490C>T NP_001394291.1:p.His164Tyr missense NR_176256.1:n.579C>T NR_176257.1:n.579C>T NR_176258.1:n.579C>T NR_176259.1:n.579C>T NR_176260.1:n.579C>T NR_176261.1:n.579C>T NC_000002.12:g.47795926C>T NC_000002.11:g.48023065C>T NG_007111.1:g.17780C>T LRG_219:g.17780C>T LRG_219t1:c.490C>T LRG_219p1:p.His164Tyr - Protein change
- H108Y, H196Y, H138Y, H164Y, H166Y, H65Y
- Other names
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- Canonical SPDI
- NC_000002.12:47795925: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. |
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| MSH6 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
9161 | 9479 | |
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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Apr 18, 2023 | RCV003443038.1 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Jun 16, 2023 | RCV003759133.2 | |
| Uncertain significance (1) |
criteria provided, single submitter
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Oct 4, 2019 | RCV002340689.2 | |
| Uncertain significance (1) |
criteria provided, single submitter
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Mar 9, 2023 | RCV004005679.2 |
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
(Mar 09, 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: SCV004829286.1
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)
|
Comment:
This missense variant replaces histidine with tyrosine at codon 164 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces histidine with tyrosine at codon 164 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MSH6-related disorders in the literature. This variant has been identified in 1/246186 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: 1
|
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Uncertain significance
(Oct 04, 2019)
|
criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002645414.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.H164Y variant (also known as c.490C>T), located in coding exon 3 of the MSH6 gene, results from a C to T substitution at nucleotide … (more)
The p.H164Y variant (also known as c.490C>T), located in coding exon 3 of the MSH6 gene, results from a C to T substitution at nucleotide position 490. The histidine at codon 164 is replaced by tyrosine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
|
|
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Uncertain significance
(Apr 18, 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: SCV004168045.1
First in ClinVar: Nov 25, 2023 Last updated: Nov 25, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 33516942) (less)
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Uncertain significance
(Jun 16, 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
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004471841.1
First in ClinVar: Feb 20, 2024 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 protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MSH6 protein function. ClinVar contains an entry for this variant (Variation ID: 1744033). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This variant is present in population databases (rs568685193, gnomAD 0.003%). This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 164 of the MSH6 protein (p.His164Tyr). (less)
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Comment:
Comment:
The p.H164Y variant (also known as c.490C>T), located in coding exon 3 of the MSH6 gene, results from a C to T substitution at nucleotide position 490. The histidine at codon 164 is replaced by tyrosine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 33516942)
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 protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MSH6 protein function. ClinVar contains an entry for this variant (Variation ID: 1744033). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This variant is present in population databases (rs568685193, gnomAD 0.003%). This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 164 of the MSH6 protein (p.His164Tyr).
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 missense variant replaces histidine with tyrosine at codon 164 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MSH6-related disorders in the literature. This variant has been identified in 1/246186 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.
Comment:
The p.H164Y variant (also known as c.490C>T), located in coding exon 3 of the MSH6 gene, results from a C to T substitution at nucleotide position 490. The histidine at codon 164 is replaced by tyrosine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 33516942)
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 protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MSH6 protein function. ClinVar contains an entry for this variant (Variation ID: 1744033). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This variant is present in population databases (rs568685193, gnomAD 0.003%). This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 164 of the MSH6 protein (p.His164Tyr).
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.