The c.843_844insAC variant, located in coding exon 4 of the MSH6 gene, results from an insertion of two nucleotides at position 843, causing a translational frameshift with a predicted alternate stop codon (p.V282Tfs*10). This alteration was identified in one Icelandic patient with right sided colon cancer that showed loss of MSH6 protein on IHC (Haraldsdottir S et al. Nat Commun, 2017 05;8:14755). In addition to the clinical data presented in the literature, 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.
ClinVar Genomic variation as it relates to human health
NM_000179.3(MSH6):c.843_844insAC (p.Val282fs)
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
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.843_844insAC (p.Val282fs)
Variation ID: 1763360 Accession: VCV001763360.20
- Type and length
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Insertion, 2 bp
- Location
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Cytogenetic: 2p16.3 2: 47798826-47798827 (GRCh38) [ NCBI UCSC ] 2: 48025965-48025966 (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 Aug 10, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000179.3:c.843_844insAC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000170.1:p.Val282fs frameshift NM_001281492.2:c.453_454insAC NP_001268421.1:p.Val152fs frameshift NM_001281493.2:c.-64_-63insAC 5 prime UTR NM_001281494.2:c.-64_-63insAC 5 prime UTR NM_001406795.1:c.939_940insAC NP_001393724.1:p.Val314Thrfs frameshift NM_001406796.1:c.843_844insAC NP_001393725.1:p.Val282Thrfs frameshift NM_001406797.1:c.546_547insAC NP_001393726.1:p.Val183Thrfs frameshift NM_001406798.1:c.843_844insAC NP_001393727.1:p.Val282Thrfs frameshift NM_001406799.1:c.318_319insAC NP_001393728.1:p.Val107Thrfs frameshift NM_001406800.1:c.843_844insAC NP_001393729.1:p.Val282Thrfs frameshift NM_001406801.1:c.546_547insAC NP_001393730.1:p.Val183Thrfs frameshift NM_001406802.1:c.939_940insAC NP_001393731.1:p.Val314Thrfs frameshift NM_001406803.1:c.843_844insAC NP_001393732.1:p.Val282Thrfs frameshift NM_001406804.1:c.765_766insAC NP_001393733.1:p.Val256Thrfs frameshift NM_001406805.1:c.546_547insAC NP_001393734.1:p.Val183Thrfs frameshift NM_001406806.1:c.318_319insAC NP_001393735.1:p.Val107Thrfs frameshift NM_001406807.1:c.318_319insAC NP_001393736.1:p.Val107Thrfs frameshift NM_001406808.1:c.843_844insAC NP_001393737.1:p.Val282Thrfs frameshift NM_001406809.1:c.843_844insAC NP_001393738.1:p.Val282Thrfs frameshift NM_001406811.1:c.-64_-63insAC NM_001406812.1:c.-64_-63insAC NM_001406813.1:c.849_850insAC NP_001393742.1:p.Val284Thrfs frameshift NM_001406814.1:c.-64_-63insAC NM_001406815.1:c.-64_-63insAC NM_001406816.1:c.-64_-63insAC NM_001406817.1:c.843_844insAC NP_001393746.1:p.Val282Thrfs frameshift NM_001406818.1:c.546_547insAC NP_001393747.1:p.Val183Thrfs frameshift NM_001406819.1:c.546_547insAC NP_001393748.1:p.Val183Thrfs frameshift NM_001406820.1:c.546_547insAC NP_001393749.1:p.Val183Thrfs frameshift NM_001406821.1:c.546_547insAC NP_001393750.1:p.Val183Thrfs frameshift NM_001406822.1:c.546_547insAC NP_001393751.1:p.Val183Thrfs frameshift NM_001406823.1:c.-64_-63insAC NM_001406824.1:c.546_547insAC NP_001393753.1:p.Val183Thrfs frameshift NM_001406825.1:c.546_547insAC NP_001393754.1:p.Val183Thrfs frameshift NM_001406826.1:c.675_676insAC NP_001393755.1:p.Val226Thrfs frameshift NM_001406827.1:c.546_547insAC NP_001393756.1:p.Val183Thrfs frameshift NM_001406828.1:c.546_547insAC NP_001393757.1:p.Val183Thrfs frameshift NM_001406829.1:c.-64_-63insAC NM_001406830.1:c.546_547insAC NP_001393759.1:p.Val183Thrfs frameshift NR_176257.1:n.932_933insAC NR_176258.1:n.932_933insAC NR_176259.1:n.932_933insAC NR_176261.1:n.932_933insAC NC_000002.12:g.47798826_47798827insAC NC_000002.11:g.48025965_48025966insAC NG_007111.1:g.20680_20681insAC LRG_219:g.20680_20681insAC LRG_219t1:c.843_844insAC LRG_219p1:p.Val282Thrfs - Protein change
- V152fs, V282fs
- Other names
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- Canonical SPDI
- NC_000002.12:47798826::AC
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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 |
9158 | 9474 | |
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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Dec 15, 2022 | RCV002445913.10 | |
| Pathogenic (2) |
criteria provided, single submitter
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Aug 10, 2023 | RCV003454217.2 |
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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Pathogenic
(Dec 15, 2022)
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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: SCV002678373.3
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.843_844insAC variant, located in coding exon 4 of the MSH6 gene, results from an insertion of two nucleotides at position 843, causing a translational … (more)
The c.843_844insAC variant, located in coding exon 4 of the MSH6 gene, results from an insertion of two nucleotides at position 843, causing a translational frameshift with a predicted alternate stop codon (p.V282Tfs*10). This alteration was identified in one Icelandic patient with right sided colon cancer that showed loss of MSH6 protein on IHC (Haraldsdottir S et al. Nat Commun, 2017 05;8:14755). In addition to the clinical data presented in the literature, 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)
|
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Pathogenic
(Aug 10, 2023)
|
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: SCV004188261.1
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
(Jul 21, 2023)
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no assertion criteria provided
Method: research
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Lynch syndrome 5
Affected status: yes
Allele origin:
germline
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deCODE genetics, Amgen
Accession: SCV004022214.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
Comment:
The variant NM_000179.3:c.843_844insAC (chr2:47798826) in MSH6 was detected in 5 heterozygotes out of 58K WGS Icelanders (MAF= 0,004%). This variant has not been reported in … (more)
The variant NM_000179.3:c.843_844insAC (chr2:47798826) in MSH6 was detected in 5 heterozygotes out of 58K WGS Icelanders (MAF= 0,004%). This variant has not been reported in ClinVar previously. Based on ACMG criteria (PVS1, PM2) this variant classifies as likely pathogenic. (less)
Number of individuals with the variant: 10
Ethnicity/Population group: Icelandic
|
Comment:
Comment:
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Comment:
The variant NM_000179.3:c.843_844insAC (chr2:47798826) in MSH6 was detected in 5 heterozygotes out of 58K WGS Icelanders (MAF= 0,004%). This variant has not been reported in ClinVar previously. Based on ACMG criteria (PVS1, PM2) this variant classifies as likely 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:
The c.843_844insAC variant, located in coding exon 4 of the MSH6 gene, results from an insertion of two nucleotides at position 843, causing a translational frameshift with a predicted alternate stop codon (p.V282Tfs*10). This alteration was identified in one Icelandic patient with right sided colon cancer that showed loss of MSH6 protein on IHC (Haraldsdottir S et al. Nat Commun, 2017 05;8:14755). In addition to the clinical data presented in the literature, 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.
Comment:
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Comment:
The variant NM_000179.3:c.843_844insAC (chr2:47798826) in MSH6 was detected in 5 heterozygotes out of 58K WGS Icelanders (MAF= 0,004%). This variant has not been reported in ClinVar previously. Based on ACMG criteria (PVS1, PM2) this variant classifies as likely pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Comprehensive population-wide analysis of Lynch syndrome in Iceland reveals founder mutations in MSH6 and PMS2. | Haraldsdottir S | Nature communications | 2017 | PMID: 28466842 |
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.