This sequence change creates a premature translational stop signal (p.Gly1265Argfs*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). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000179.3(MSH6):c.3792dup (p.Gly1265fs)
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.
Pathogenic/Likely pathogenic
3
criteria provided, multiple submitters, no conflicts
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.3792dup (p.Gly1265fs)
Variation ID: 1996563 Accession: VCV001996563.5
- Type and length
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Duplication, 1 bp
- Location
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Cytogenetic: 2p16.3 2: 47806348-47806349 (GRCh38) [ NCBI UCSC ] 2: 48033487-48033488 (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 May 1, 2024 Oct 25, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000179.3:c.3792dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000170.1:p.Gly1265fs frameshift NM_000179.2:c.3792dupA NM_001281492.2:c.3402dup NP_001268421.1:p.Gly1135fs frameshift NM_001281493.2:c.2886dup NP_001268422.1:p.Gly963fs frameshift NM_001281494.2:c.2886dup NP_001268423.1:p.Gly963fs frameshift NM_001406795.1:c.3888dup NP_001393724.1:p.Gly1297Argfs frameshift NM_001406796.1:c.3792dup NP_001393725.1:p.Gly1265Argfs frameshift NM_001406797.1:c.3495dup NP_001393726.1:p.Gly1166Argfs frameshift NM_001406798.1:c.3618dup NP_001393727.1:p.Gly1207Argfs frameshift NM_001406799.1:c.3267dup NP_001393728.1:p.Gly1090Argfs frameshift NM_001406800.1:c.3792dup NP_001393729.1:p.Gly1265Argfs frameshift NM_001406801.1:c.3495dup NP_001393730.1:p.Gly1166Argfs frameshift NM_001406802.1:c.3888dup NP_001393731.1:p.Gly1297Argfs frameshift NM_001406803.1:c.2928dup NP_001393732.1:p.Gly977Argfs frameshift NM_001406804.1:c.3714dup NP_001393733.1:p.Gly1239Argfs frameshift NM_001406805.1:c.3495dup NP_001393734.1:p.Gly1166Argfs frameshift NM_001406806.1:c.3267dup NP_001393735.1:p.Gly1090Argfs frameshift NM_001406807.1:c.3267dup NP_001393736.1:p.Gly1090Argfs frameshift NM_001406808.1:c.3792dup NP_001393737.1:p.Gly1265Argfs frameshift NM_001406809.1:c.3792dup NP_001393738.1:p.Gly1265Argfs frameshift NM_001406811.1:c.2886dup NP_001393740.1:p.Gly963Argfs frameshift NM_001406812.1:c.2886dup NP_001393741.1:p.Gly963Argfs frameshift NM_001406813.1:c.3798dup NP_001393742.1:p.Gly1267Argfs frameshift NM_001406814.1:c.2886dup NP_001393743.1:p.Gly963Argfs frameshift NM_001406815.1:c.2886dup NP_001393744.1:p.Gly963Argfs frameshift NM_001406816.1:c.2886dup NP_001393745.1:p.Gly963Argfs frameshift NM_001406817.1:c.2226dup NP_001393746.1:p.Gly743Argfs frameshift NM_001406818.1:c.3495dup NP_001393747.1:p.Gly1166Argfs frameshift NM_001406819.1:c.3495dup NP_001393748.1:p.Gly1166Argfs frameshift NM_001406820.1:c.3495dup NP_001393749.1:p.Gly1166Argfs frameshift NM_001406821.1:c.3495dup NP_001393750.1:p.Gly1166Argfs frameshift NM_001406822.1:c.3495dup NP_001393751.1:p.Gly1166Argfs frameshift NM_001406823.1:c.2886dup NP_001393752.1:p.Gly963Argfs frameshift NM_001406824.1:c.3495dup NP_001393753.1:p.Gly1166Argfs frameshift NM_001406825.1:c.3495dup NP_001393754.1:p.Gly1166Argfs frameshift NM_001406826.1:c.3624dup NP_001393755.1:p.Gly1209Argfs frameshift NM_001406827.1:c.3495dup NP_001393756.1:p.Gly1166Argfs frameshift NM_001406828.1:c.3495dup NP_001393757.1:p.Gly1166Argfs frameshift NM_001406829.1:c.2886dup NP_001393758.1:p.Gly963Argfs frameshift NM_001406830.1:c.3495dup NP_001393759.1:p.Gly1166Argfs frameshift NM_001406831.1:c.573dup NP_001393760.1:p.Gly192Argfs frameshift NM_001406832.1:c.639dup NP_001393761.1:p.Gly214Argfs frameshift NM_001407362.1:c.1737dup NP_001394291.1:p.Gly580Argfs frameshift NR_176256.1:n.2722dup NR_176257.1:n.4053dup NR_176258.1:n.3982dup NR_176259.1:n.3881dup NR_176260.1:n.1826dup NR_176261.1:n.3763dup NC_000002.12:g.47806349dup NC_000002.11:g.48033488dup NG_007111.1:g.28203dup NG_008397.1:g.104327dup LRG_219:g.28203dup LRG_219t1:c.3792dup LRG_219p1:p.Gly1265Argfs - Protein change
- G963fs, G1135fs, G1265fs
- Other names
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- Canonical SPDI
- NC_000002.12:47806348:A:AA
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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
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May 19, 2022 | RCV002806856.3 | |
| Likely pathogenic (1) |
criteria provided, single submitter
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May 4, 2022 | RCV003146643.3 | |
| Pathogenic (1) |
criteria provided, single submitter
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Oct 25, 2023 | RCV004064883.1 |
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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Likely pathogenic
(May 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003833616.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(May 19, 2022)
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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: SCV003200057.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Gly1265Argfs*10) in the MSH6 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Gly1265Argfs*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). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Pathogenic
(Oct 25, 2023)
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criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV005033372.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
The c.3792dupA pathogenic mutation, located in coding exon 8 of the MSH6 gene, results from a duplication of A at nucleotide position 3792, causing a … (more)
The c.3792dupA pathogenic mutation, located in coding exon 8 of the MSH6 gene, results from a duplication of A at nucleotide position 3792, causing a translational frameshift with a predicted alternate stop codon (p.G1265Rfs*10). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
|
Comment:
Comment:
The c.3792dupA pathogenic mutation, located in coding exon 8 of the MSH6 gene, results from a duplication of A at nucleotide position 3792, causing a translational frameshift with a predicted alternate stop codon (p.G1265Rfs*10). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
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 creates a premature translational stop signal (p.Gly1265Argfs*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). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.3792dupA pathogenic mutation, located in coding exon 8 of the MSH6 gene, results from a duplication of A at nucleotide position 3792, causing a translational frameshift with a predicted alternate stop codon (p.G1265Rfs*10). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
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.