ClinVar Genomic variation as it relates to human health
NM_000179.3(MSH6):c.4001G>C (p.Arg1334Pro)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000179.3(MSH6):c.4001G>C (p.Arg1334Pro)
Variation ID: 233214 Accession: VCV000233214.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p16.3 2: 47806651 (GRCh38) [ NCBI UCSC ] 2: 48033790 (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 May 29, 2016 May 1, 2024 Aug 11, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000179.3:c.4001G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000170.1:p.Arg1334Pro missense NM_001281492.2:c.3611G>C NP_001268421.1:p.Arg1204Pro missense NM_001281493.2:c.3095G>C NP_001268422.1:p.Arg1032Pro missense NM_001281494.2:c.3095G>C NP_001268423.1:p.Arg1032Pro missense NC_000002.12:g.47806651G>C NC_000002.11:g.48033790G>C NG_007111.1:g.28505G>C NG_008397.1:g.104025C>G LRG_219:g.28505G>C LRG_219t1:c.4001G>C LRG_219p1:p.Arg1334Pro - Protein change
- R1334P, R1204P, R1032P
- Other names
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- Canonical SPDI
- NC_000002.12:47806650:G:C
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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
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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 |
9153 | 9466 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
criteria provided, single submitter
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May 30, 2022 | RCV000219938.4 | |
no classifications from unflagged records (1) |
no classifications from unflagged records
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Jun 27, 2024 | RCV000459481.10 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Aug 11, 2023 | RCV001810439.4 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Mar 10, 2023 | RCV003316228.2 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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
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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
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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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Likely pathogenic
(Jan 12, 2022)
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criteria provided, single submitter
Method: clinical testing
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Lynch Syndrome
Affected status: yes
Allele origin:
germline
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Diagnostic Molecular Genetics Laboratory, Memorial Sloan Kettering Cancer Center
Accession: SCV002060005.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
The heterozygous germline variant, MSH6 c.4001G>C changes an Arginine to Proline at amino acid position 1334 (p.Arg1334Pro) and affects the last nucleotide of exon 9. … (more)
The heterozygous germline variant, MSH6 c.4001G>C changes an Arginine to Proline at amino acid position 1334 (p.Arg1334Pro) and affects the last nucleotide of exon 9. This variant is absent from large population databases (1000 Genomes, ESP, and Broad ExAc). Computational prediction tools (SpliceSiteFinder, MaxEntScan, NNSPLICE and GeneSplicer) predict a complete loss of the intron 9 canonical splice donor site. Our functional study by RNA analysis (DMG internal data) demonstrated that this variant completely abolished normal splicing and caused exon 9 skipping, which is expected to lead to a prematurely truncated or abnormal protein. Our results indicate that this variant likely contributes to cancer predisposition through disruption of normal splicing, and is classified as likely pathogenic. (less)
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Pathogenic
(May 30, 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: SCV000277547.7
First in ClinVar: May 29, 2016 Last updated: May 01, 2024 |
Comment:
The c.4001G>C pathogenic mutation (also known as p.R1334P), located in coding exon 9 of the MSH6 gene, results from a G to C substitution at … (more)
The c.4001G>C pathogenic mutation (also known as p.R1334P), located in coding exon 9 of the MSH6 gene, results from a G to C substitution at nucleotide position 4001. The amino acid change results in arginine to proline at codon 1334, an amino acid with dissimilar properties. However, this change occurs in the last base pair of coding exon 9, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is well conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Another alteration impacting the same donor site (c.4001G>A) has been shown to have a similar impact on splicing identified in several probands, one of whom has a Lynch syndrome-associated tumor that demonstrated loss of MSH6 expression by immunohistochemistry (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(May 13, 2022)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002761772.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
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Likely pathogenic
(Mar 10, 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: SCV004018087.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 36691871]. mRNA analysis has … (more)
This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 36691871]. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 36691871]. (less)
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Likely pathogenic
(Aug 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV004024268.1
First in ClinVar: Aug 13, 2023 Last updated: Aug 13, 2023 |
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Uncertain significance
(Dec 15, 2020)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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Hereditary nonpolyposis colorectal neoplasms
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000551274.8
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
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 … (more)
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. This variant disrupts the c.4001G nucleotide in the MSH6 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 10508506, 17453009, 21836479, 18415027). This suggests that this nucleotide is clinically-significant, and that variants that disrupt this position are likely to be disease-causing. Nucleotide substitutions within 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, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 233214). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with proline at codon 1334 of the MSH6 protein (p.Arg1334Pro). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and proline. This variant also falls at the last nucleotide of exon 9 of the MSH6 coding sequence, which is part of the consensus splice site for this exon. (less)
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Characterization of a germline variant MSH6 c.4001G > C in a Lynch syndrome family. | Yang C | Molecular genetics & genomic medicine | 2023 | PMID: 36691871 |
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 |
Genome-wide copy neutral LOH is infrequent in familial and sporadic microsatellite unstable carcinomas. | van Puijenbroek M | Familial cancer | 2008 | PMID: 18415027 |
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 |
Patients with an unexplained microsatellite instable tumour have a low risk of familial cancer. | Overbeek LI | British journal of cancer | 2007 | PMID: 17453009 |
Familial endometrial cancer in female carriers of MSH6 germline mutations. | Wijnen J | Nature genetics | 1999 | PMID: 10508506 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Text-mined citations for rs267608122 ...
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.