This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
ClinVar Genomic variation as it relates to human health
NM_000179.3(MSH6):c.3959dup (p.Arg1321fs)
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.
(2)
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
2
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.3959dup (p.Arg1321fs)
Variation ID: 2673616 Accession: VCV002673616.2
- Type and length
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Duplication, 1 bp
- Location
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Cytogenetic: 2p16.3 2: 47806608-47806609 (GRCh38) [ NCBI UCSC ] 2: 48033747-48033748 (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 Dec 25, 2023 May 1, 2024 Sep 25, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000179.3:c.3959dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000170.1:p.Arg1321fs frameshift NM_000179.2:c.3959dupC NM_001281492.2:c.3569dup NP_001268421.1:p.Arg1191fs frameshift NM_001281493.2:c.3053dup NP_001268422.1:p.Arg1019fs frameshift NM_001281494.2:c.3053dup NP_001268423.1:p.Arg1019fs frameshift NM_001406795.1:c.4055dup NP_001393724.1:p.Arg1353fs frameshift NM_001406796.1:c.3959dup NP_001393725.1:p.Arg1321fs frameshift NM_001406797.1:c.3662dup NP_001393726.1:p.Arg1222fs frameshift NM_001406798.1:c.3785dup NP_001393727.1:p.Arg1263fs frameshift NM_001406799.1:c.3434dup NP_001393728.1:p.Arg1146fs frameshift NM_001406800.1:c.3946dup NP_001393729.1:p.Gln1316fs frameshift NM_001406801.1:c.3662dup NP_001393730.1:p.Arg1222fs frameshift NM_001406802.1:c.3898-170dup intron variant NM_001406803.1:c.3095dup NP_001393732.1:p.Arg1033fs frameshift NM_001406804.1:c.3881dup NP_001393733.1:p.Arg1295fs frameshift NM_001406805.1:c.3662dup NP_001393734.1:p.Arg1222fs frameshift NM_001406806.1:c.3434dup NP_001393735.1:p.Arg1146fs frameshift NM_001406807.1:c.3434dup NP_001393736.1:p.Arg1146fs frameshift NM_001406808.1:c.3959dup NP_001393737.1:p.Arg1321fs frameshift NM_001406809.1:c.3959dup NP_001393738.1:p.Arg1321fs frameshift NM_001406811.1:c.3053dup NP_001393740.1:p.Arg1019fs frameshift NM_001406812.1:c.3053dup NP_001393741.1:p.Arg1019fs frameshift NM_001406813.1:c.3965dup NP_001393742.1:p.Arg1323fs frameshift NM_001406814.1:c.3053dup NP_001393743.1:p.Arg1019fs frameshift NM_001406815.1:c.3053dup NP_001393744.1:p.Arg1019fs frameshift NM_001406816.1:c.3053dup NP_001393745.1:p.Arg1019fs frameshift NM_001406817.1:c.2393dup NP_001393746.1:p.Arg799fs frameshift NM_001406818.1:c.3662dup NP_001393747.1:p.Arg1222fs frameshift NM_001406819.1:c.3662dup NP_001393748.1:p.Arg1222fs frameshift NM_001406820.1:c.3662dup NP_001393749.1:p.Arg1222fs frameshift NM_001406821.1:c.3662dup NP_001393750.1:p.Arg1222fs frameshift NM_001406822.1:c.3662dup NP_001393751.1:p.Arg1222fs frameshift NM_001406823.1:c.3053dup NP_001393752.1:p.Arg1019fs frameshift NM_001406824.1:c.3662dup NP_001393753.1:p.Arg1222fs frameshift NM_001406825.1:c.3662dup NP_001393754.1:p.Arg1222fs frameshift NM_001406826.1:c.3791dup NP_001393755.1:p.Arg1265fs frameshift NM_001406827.1:c.3662dup NP_001393756.1:p.Arg1222fs frameshift NM_001406828.1:c.3662dup NP_001393757.1:p.Arg1222fs frameshift NM_001406829.1:c.3053dup NP_001393758.1:p.Arg1019fs frameshift NM_001406830.1:c.3662dup NP_001393759.1:p.Arg1222fs frameshift NM_001406831.1:c.740dup NP_001393760.1:p.Arg248fs frameshift NM_001406832.1:c.806dup NP_001393761.1:p.Arg270fs frameshift NM_001407362.1:c.1904dup NP_001394291.1:p.Arg636fs frameshift NR_176256.1:n.2889dup non-coding transcript variant NR_176257.1:n.4220dup non-coding transcript variant NR_176258.1:n.4149dup non-coding transcript variant NR_176259.1:n.4048dup non-coding transcript variant NR_176260.1:n.1993dup NR_176261.1:n.3930dup non-coding transcript variant NC_000002.12:g.47806609dup NC_000002.11:g.48033748dup NG_007111.1:g.28463dup NG_008397.1:g.104067dup LRG_219:g.28463dup LRG_219t1:c.3959dup LRG_219p1:p.Arg1321Lysfs - Protein change
- Q1316fs, R1019fs, R1033fs, R1146fs, R1191fs, R1222fs, R1263fs, R1265fs, R1295fs, R1321fs, R1323fs, R1353fs, R248fs, R270fs, R636fs, R799fs
- Other names
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- Canonical SPDI
- NC_000002.12:47806608:C:CC
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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. |
|---|---|---|---|---|
| Pathogenic (1) |
criteria provided, single submitter
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Aug 28, 2023 | RCV003450253.1 | |
| Likely pathogenic (1) |
criteria provided, single submitter
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Sep 25, 2023 | RCV004364746.1 |
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
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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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Pathogenic
(Aug 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 5
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004185703.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
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Likely pathogenic
(Sep 25, 2023)
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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: SCV005032958.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
The c.3959dupC variant, located in coding exon 9 of the MSH6 gene, results from a duplication of C at nucleotide position 3959, causing a translational … (more)
The c.3959dupC variant, located in coding exon 9 of the MSH6 gene, results from a duplication of C at nucleotide position 3959, causing a translational frameshift with a predicted alternate stop codon (p.R1321Kfs*4). This alteration occurs at the 3' terminus of MSH6 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 40 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Comment:
Comment:
The c.3959dupC variant, located in coding exon 9 of the MSH6 gene, results from a duplication of C at nucleotide position 3959, causing a translational frameshift with a predicted alternate stop codon (p.R1321Kfs*4). This alteration occurs at the 3' terminus of MSH6 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 40 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
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 variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Comment:
The c.3959dupC variant, located in coding exon 9 of the MSH6 gene, results from a duplication of C at nucleotide position 3959, causing a translational frameshift with a predicted alternate stop codon (p.R1321Kfs*4). This alteration occurs at the 3' terminus of MSH6 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 40 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
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 Oct 08, 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.