For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.His1250Leufs*10) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816).
ClinVar Genomic variation as it relates to human health
NM_000179.3(MSH6):c.3749_3764del (p.His1250fs)
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.
Pathogenic
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.3749_3764del (p.His1250fs)
Variation ID: 2104466 Accession: VCV002104466.2
- Type and length
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Deletion, 16 bp
- Location
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Cytogenetic: 2p16.3 2: 47806306-47806321 (GRCh38) [ NCBI UCSC ] 2: 48033445-48033460 (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 8, 2023 Feb 20, 2024 Feb 28, 2022 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000179.3:c.3749_3764del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000170.1:p.His1250fs frameshift NM_001281492.2:c.3359_3374del NP_001268421.1:p.His1120fs frameshift NM_001281493.2:c.2843_2858del NP_001268422.1:p.His948fs frameshift NM_001281494.2:c.2843_2858del NP_001268423.1:p.His948fs frameshift NM_001406795.1:c.3845_3860del16 NP_001393724.1:p.His1282Leufs frameshift NM_001406796.1:c.3749_3764del16 NP_001393725.1:p.His1250Leufs frameshift NM_001406797.1:c.3452_3467del16 NP_001393726.1:p.His1151Leufs frameshift NM_001406798.1:c.3575_3590del16 NP_001393727.1:p.His1192Leufs frameshift NM_001406799.1:c.3224_3239del16 NP_001393728.1:p.His1075Leufs frameshift NM_001406800.1:c.3749_3764del16 NP_001393729.1:p.His1250Leufs frameshift NM_001406801.1:c.3452_3467del16 NP_001393730.1:p.His1151Leufs frameshift NM_001406802.1:c.3845_3860del16 NP_001393731.1:p.His1282Leufs frameshift NM_001406803.1:c.2885_2900del16 NP_001393732.1:p.His962Leufs frameshift NM_001406804.1:c.3671_3686del16 NP_001393733.1:p.His1224Leufs frameshift NM_001406805.1:c.3452_3467del16 NP_001393734.1:p.His1151Leufs frameshift NM_001406806.1:c.3224_3239del16 NP_001393735.1:p.His1075Leufs frameshift NM_001406807.1:c.3224_3239del16 NP_001393736.1:p.His1075Leufs frameshift NM_001406808.1:c.3749_3764del16 NP_001393737.1:p.His1250Leufs frameshift NM_001406809.1:c.3749_3764del16 NP_001393738.1:p.His1250Leufs frameshift NM_001406811.1:c.2843_2858del16 NP_001393740.1:p.His948Leufs frameshift NM_001406812.1:c.2843_2858del16 NP_001393741.1:p.His948Leufs frameshift NM_001406813.1:c.3755_3770del16 NP_001393742.1:p.His1252Leufs frameshift NM_001406814.1:c.2843_2858del16 NP_001393743.1:p.His948Leufs frameshift NM_001406815.1:c.2843_2858del16 NP_001393744.1:p.His948Leufs frameshift NM_001406816.1:c.2843_2858del16 NP_001393745.1:p.His948Leufs frameshift NM_001406817.1:c.2183_2198del16 NP_001393746.1:p.His728Leufs frameshift NM_001406818.1:c.3452_3467del16 NP_001393747.1:p.His1151Leufs frameshift NM_001406819.1:c.3452_3467del16 NP_001393748.1:p.His1151Leufs frameshift NM_001406820.1:c.3452_3467del16 NP_001393749.1:p.His1151Leufs frameshift NM_001406821.1:c.3452_3467del16 NP_001393750.1:p.His1151Leufs frameshift NM_001406822.1:c.3452_3467del16 NP_001393751.1:p.His1151Leufs frameshift NM_001406823.1:c.2843_2858del16 NP_001393752.1:p.His948Leufs frameshift NM_001406824.1:c.3452_3467del16 NP_001393753.1:p.His1151Leufs frameshift NM_001406825.1:c.3452_3467del16 NP_001393754.1:p.His1151Leufs frameshift NM_001406826.1:c.3581_3596del16 NP_001393755.1:p.His1194Leufs frameshift NM_001406827.1:c.3452_3467del16 NP_001393756.1:p.His1151Leufs frameshift NM_001406828.1:c.3452_3467del16 NP_001393757.1:p.His1151Leufs frameshift NM_001406829.1:c.2843_2858del16 NP_001393758.1:p.His948Leufs frameshift NM_001406830.1:c.3452_3467del16 NP_001393759.1:p.His1151Leufs frameshift NM_001406831.1:c.530_545del16 NP_001393760.1:p.His177Leufs frameshift NM_001406832.1:c.596_611del16 NP_001393761.1:p.His199Leufs frameshift NM_001407362.1:c.1694_1709del16 NP_001394291.1:p.His565Leufs frameshift NR_176256.1:n.2679_2694del16 NR_176257.1:n.4010_4025del16 NR_176258.1:n.3939_3954del16 NR_176259.1:n.3838_3853del16 NR_176260.1:n.1783_1798del16 NR_176261.1:n.3720_3735del16 NC_000002.12:g.47806306_47806321del NC_000002.11:g.48033445_48033460del NG_007111.1:g.28160_28175del NG_008397.1:g.104355_104370del LRG_219:g.28160_28175del LRG_219t1:c.3749_3764del16 LRG_219p1:p.His1250Leufs - Protein change
- H1120fs, H948fs, H1250fs
- Other names
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- Canonical SPDI
- NC_000002.12:47806305:ATTCATTAGTAGAAGA:
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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. |
|---|---|---|---|---|
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 28, 2022 | RCV003031391.3 |
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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Pathogenic
(Feb 28, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary nonpolyposis colorectal neoplasms
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003318782.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with MSH6-related conditions. … (more)
For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.His1250Leufs*10) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). (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:
For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.His1250Leufs*10) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database. | Thompson BA | Nature genetics | 2014 | PMID: 24362816 |
| Germline MSH6 mutations are more prevalent in endometrial cancer patient cohorts than hereditary non polyposis colorectal cancer cohorts. | Devlin LA | The Ulster medical journal | 2008 | PMID: 18269114 |
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.