This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.
ClinVar Genomic variation as it relates to human health
NM_000179.3(MSH6):c.4001+1G>A
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.
(4)
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.
Conflicting classifications of pathogenicity
Pathogenic(1); Likely pathogenic(1); Uncertain significance(1)
Pathogenic(1); Likely pathogenic(1); Uncertain significance(1)
4
criteria provided, conflicting classifications
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.4001+1G>A
Variation ID: 1320037 Accession: VCV001320037.5
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p16.3 2: 47806652 (GRCh38) [ NCBI UCSC ] 2: 48033791 (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 11, 2021 May 1, 2024 Aug 29, 2023 - HGVS
- ... more HGVS ... less HGVS
- Protein change
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- Other names
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- Canonical SPDI
- NC_000002.12:47806651:G:A
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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. |
|---|---|---|---|---|
| Likely pathogenic (2) |
criteria provided, single submitter
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Aug 29, 2023 | RCV001775212.2 | |
| Pathogenic (1) |
criteria provided, single submitter
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Sep 8, 2021 | RCV002370312.2 | |
| Uncertain significance (1) |
criteria provided, single submitter
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Aug 19, 2023 | RCV003594156.2 |
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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|---|---|---|---|---|---|
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Likely pathogenic
(Aug 29, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome 5
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004189282.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either … (more)
This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. (less)
|
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Uncertain significance
(Aug 19, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary nonpolyposis colorectal neoplasms
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004293923.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 1320037). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing … (more)
ClinVar contains an entry for this variant (Variation ID: 1320037). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Disruption of this splice site has been observed in individual(s) with Lynch syndrome (PMID: 18566915, 21836479). It has also been observed to segregate with disease in related individuals. This sequence change affects a donor splice site in intron 9 of the MSH6 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is not present in population databases (gnomAD no frequency). (less)
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Pathogenic
(Sep 08, 2021)
|
criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002625345.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.4001+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 9 of the MSH6 gene. Another alteration impacting … (more)
The c.4001+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 9 of the MSH6 gene. Another alteration impacting the same donor site (c.4001+2T>C) has been described in several Danish HNPCC/Lynch syndrome families (Nilbert M et al. Fam. Cancer 2009;8(1):75-83; Jensen UB et al. Breast Cancer Res. Treat., 2010 Apr;120:777-82; Okkels H et al. Appl Immunohistochem Mol Morphol. 2012 Oct;20(5):470-7; Therkildsen C et al. Eur. J. Neurol., 2015 Apr;22:717-24). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. (less)
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Likely pathogenic
(Mar 31, 2021)
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no assertion criteria provided
Method: clinical testing
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Lynch syndrome 5
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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MVZ Praenatalmedizin und Genetik Nuernberg
Accession: SCV002011883.1
First in ClinVar: Nov 11, 2021 Last updated: Nov 11, 2021 |
Comment:
This variant was not listed in the databases (ClinVar, LOVD). GnomAD shows no entry (very rare or private variant). This variant is located in the … (more)
This variant was not listed in the databases (ClinVar, LOVD). GnomAD shows no entry (very rare or private variant). This variant is located in the highly conserved splicing-consenus-locus and in silico analysis consistently predict a damaging effect. In the literature the variant was described as pathogenic for a patient (PMID:25980754). A different substitutions at c.4001+1 is listed in ClinVar as likely-pathogenic: NM_000179.3(MSH6):c.4001+1G>C. Taken together, we classify this variant as likely pathogenic. (less)
Clinical Features:
Ovarian carcinoma (present)
Age: 50-59 years
Sex: female
|
Comment:
Comment:
ClinVar contains an entry for this variant (Variation ID: 1320037). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Disruption of this splice site has been observed in individual(s) with Lynch syndrome (PMID: 18566915, 21836479). It has also been observed to segregate with disease in related individuals. This sequence change affects a donor splice site in intron 9 of the MSH6 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is not present in population databases (gnomAD no frequency).
Comment:
The c.4001+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 9 of the MSH6 gene. Another alteration impacting the same donor site (c.4001+2T>C) has been described in several Danish HNPCC/Lynch syndrome families (Nilbert M et al. Fam. Cancer 2009;8(1):75-83; Jensen UB et al. Breast Cancer Res. Treat., 2010 Apr;120:777-82; Okkels H et al. Appl Immunohistochem Mol Morphol. 2012 Oct;20(5):470-7; Therkildsen C et al. Eur. J. Neurol., 2015 Apr;22:717-24). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Comment:
This variant was not listed in the databases (ClinVar, LOVD). GnomAD shows no entry (very rare or private variant). This variant is located in the highly conserved splicing-consenus-locus and in silico analysis consistently predict a damaging effect. In the literature the variant was described as pathogenic for a patient (PMID:25980754). A different substitutions at c.4001+1 is listed in ClinVar as likely-pathogenic: NM_000179.3(MSH6):c.4001+1G>C. Taken together, we classify this variant 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:
This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.
Comment:
ClinVar contains an entry for this variant (Variation ID: 1320037). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Disruption of this splice site has been observed in individual(s) with Lynch syndrome (PMID: 18566915, 21836479). It has also been observed to segregate with disease in related individuals. This sequence change affects a donor splice site in intron 9 of the MSH6 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is not present in population databases (gnomAD no frequency).
Comment:
The c.4001+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 9 of the MSH6 gene. Another alteration impacting the same donor site (c.4001+2T>C) has been described in several Danish HNPCC/Lynch syndrome families (Nilbert M et al. Fam. Cancer 2009;8(1):75-83; Jensen UB et al. Breast Cancer Res. Treat., 2010 Apr;120:777-82; Okkels H et al. Appl Immunohistochem Mol Morphol. 2012 Oct;20(5):470-7; Therkildsen C et al. Eur. J. Neurol., 2015 Apr;22:717-24). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Comment:
This variant was not listed in the databases (ClinVar, LOVD). GnomAD shows no entry (very rare or private variant). This variant is located in the highly conserved splicing-consenus-locus and in silico analysis consistently predict a damaging effect. In the literature the variant was described as pathogenic for a patient (PMID:25980754). A different substitutions at c.4001+1 is listed in ClinVar as likely-pathogenic: NM_000179.3(MSH6):c.4001+1G>C. Taken together, we classify this variant as likely pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. | Yurgelun MB | Gastroenterology | 2015 | PMID: 25980754 |
| Challenges in the identification of MSH6-associated colorectal cancer: rectal location, less typical histology, and a subset with retained mismatch repair function. | Klarskov L | The American journal of surgical pathology | 2011 | PMID: 21836479 |
| Major contribution from recurrent alterations and MSH6 mutations in the Danish Lynch syndrome population. | Nilbert M | Familial cancer | 2009 | PMID: 18566915 |
| Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
| Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Text-mined citations for rs1114167729 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record 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.