The c.3957_3958dupAG variant, located in coding exon 9 of the MSH6 gene, results from a duplication of AG at nucleotide position 3957, causing a translational frameshift with a predicted alternate stop codon (p.A1320Efs*8). This alteration occurs at the 3' terminus of theMSH6 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 41 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function based on an internal structural analysis indicating this variant disrupts a portion of the MSH2-MSH6 binding site in a region where pathogenic variants have been observed (Ambry internal data; Warren JJ et al. Mol. Cell, 2007 May;26:579-92). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000179.3(MSH6):c.3957_3958dup (p.Ala1320fs)
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.
Likely pathogenic
1
criteria provided, single submitter
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000179.3(MSH6):c.3957_3958dup (p.Ala1320fs)
Variation ID: 1736472 Accession: VCV001736472.2
- Type and length
-
Duplication, 2 bp
- Location
-
Cytogenetic: 2p16.3 2: 47806606-47806607 (GRCh38) [ NCBI UCSC ] 2: 48033745-48033746 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Jul 30, 2020 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000179.3:c.3957_3958dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000170.1:p.Ala1320fs frameshift NM_000179.2:c.3957_3958dupAG frameshift NM_001281492.2:c.3567_3568dup NP_001268421.1:p.Ala1190fs frameshift NM_001281493.2:c.3051_3052dup NP_001268422.1:p.Ala1018fs frameshift NM_001281494.2:c.3051_3052dup NP_001268423.1:p.Ala1018fs frameshift NM_001406795.1:c.4053_4054dup NP_001393724.1:p.Ala1352Glufs frameshift NM_001406796.1:c.3957_3958dup NP_001393725.1:p.Ala1320Glufs frameshift NM_001406797.1:c.3660_3661dup NP_001393726.1:p.Ala1221Glufs frameshift NM_001406798.1:c.3783_3784dup NP_001393727.1:p.Ala1262Glufs frameshift NM_001406799.1:c.3432_3433dup NP_001393728.1:p.Ala1145Glufs frameshift NM_001406800.1:c.3944_3945dup NP_001393729.1:p.Gln1316Serfs frameshift NM_001406801.1:c.3660_3661dup NP_001393730.1:p.Ala1221Glufs frameshift NM_001406803.1:c.3093_3094dup NP_001393732.1:p.Ala1032Glufs frameshift NM_001406804.1:c.3879_3880dup NP_001393733.1:p.Ala1294Glufs frameshift NM_001406805.1:c.3660_3661dup NP_001393734.1:p.Ala1221Glufs frameshift NM_001406806.1:c.3432_3433dup NP_001393735.1:p.Ala1145Glufs frameshift NM_001406807.1:c.3432_3433dup NP_001393736.1:p.Ala1145Glufs frameshift NM_001406808.1:c.3957_3958dup NP_001393737.1:p.Ala1320Glufs frameshift NM_001406809.1:c.3957_3958dup NP_001393738.1:p.Ala1320Glufs frameshift NM_001406811.1:c.3051_3052dup NP_001393740.1:p.Ala1018Glufs frameshift NM_001406812.1:c.3051_3052dup NP_001393741.1:p.Ala1018Glufs frameshift NM_001406813.1:c.3963_3964dup NP_001393742.1:p.Ala1322Glufs frameshift NM_001406814.1:c.3051_3052dup NP_001393743.1:p.Ala1018Glufs frameshift NM_001406815.1:c.3051_3052dup NP_001393744.1:p.Ala1018Glufs frameshift NM_001406816.1:c.3051_3052dup NP_001393745.1:p.Ala1018Glufs frameshift NM_001406817.1:c.2391_2392dup NP_001393746.1:p.Ala798Glufs frameshift NM_001406818.1:c.3660_3661dup NP_001393747.1:p.Ala1221Glufs frameshift NM_001406819.1:c.3660_3661dup NP_001393748.1:p.Ala1221Glufs frameshift NM_001406820.1:c.3660_3661dup NP_001393749.1:p.Ala1221Glufs frameshift NM_001406821.1:c.3660_3661dup NP_001393750.1:p.Ala1221Glufs frameshift NM_001406822.1:c.3660_3661dup NP_001393751.1:p.Ala1221Glufs frameshift NM_001406823.1:c.3051_3052dup NP_001393752.1:p.Ala1018Glufs frameshift NM_001406824.1:c.3660_3661dup NP_001393753.1:p.Ala1221Glufs frameshift NM_001406825.1:c.3660_3661dup NP_001393754.1:p.Ala1221Glufs frameshift NM_001406826.1:c.3789_3790dup NP_001393755.1:p.Ala1264Glufs frameshift NM_001406827.1:c.3660_3661dup NP_001393756.1:p.Ala1221Glufs frameshift NM_001406828.1:c.3660_3661dup NP_001393757.1:p.Ala1221Glufs frameshift NM_001406829.1:c.3051_3052dup NP_001393758.1:p.Ala1018Glufs frameshift NM_001406830.1:c.3660_3661dup NP_001393759.1:p.Ala1221Glufs frameshift NM_001406831.1:c.738_739dup NP_001393760.1:p.Ala247Glufs frameshift NM_001406832.1:c.804_805dup NP_001393761.1:p.Ala269Glufs frameshift NM_001407362.1:c.1902_1903dup NP_001394291.1:p.Ala635Glufs frameshift NR_176256.1:n.2887_2888dup NR_176257.1:n.4218_4219dup NR_176258.1:n.4147_4148dup NR_176259.1:n.4046_4047dup NR_176260.1:n.1991_1992dup NR_176261.1:n.3928_3929dup NC_000002.12:g.47806607_47806608dup NC_000002.11:g.48033746_48033747dup NG_007111.1:g.28461_28462dup NG_008397.1:g.104068_104069dup LRG_219:g.28461_28462dup LRG_219t1:c.3957_3958dup LRG_219p1:p.Ala1320Glufs - Protein change
- A1190fs, A1320fs, A1018fs
- Other names
- -
- Canonical SPDI
- NC_000002.12:47806606:AG:AGAG
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- 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. |
|||
| 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. |
|---|---|---|---|---|
| Likely pathogenic (1) |
criteria provided, single submitter
|
Jul 30, 2020 | RCV002357639.2 |
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Jul 30, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002619496.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.3957_3958dupAG variant, located in coding exon 9 of the MSH6 gene, results from a duplication of AG at nucleotide position 3957, causing a translational … (more)
The c.3957_3958dupAG variant, located in coding exon 9 of the MSH6 gene, results from a duplication of AG at nucleotide position 3957, causing a translational frameshift with a predicted alternate stop codon (p.A1320Efs*8). This alteration occurs at the 3' terminus of theMSH6 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 41 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function based on an internal structural analysis indicating this variant disrupts a portion of the MSH2-MSH6 binding site in a region where pathogenic variants have been observed (Ambry internal data; Warren JJ et al. Mol. Cell, 2007 May;26:579-92). Based on the majority of available evidence to date, this variant is likely to be pathogenic. (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 c.3957_3958dupAG variant, located in coding exon 9 of the MSH6 gene, results from a duplication of AG at nucleotide position 3957, causing a translational frameshift with a predicted alternate stop codon (p.A1320Efs*8). This alteration occurs at the 3' terminus of theMSH6 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 41 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function based on an internal structural analysis indicating this variant disrupts a portion of the MSH2-MSH6 binding site in a region where pathogenic variants have been observed (Ambry internal data; Warren JJ et al. Mol. Cell, 2007 May;26:579-92). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
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.