ClinVar Genomic variation as it relates to human health
NM_002439.5(MSH3):c.1148del (p.Lys383fs)
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
-
NM_002439.5(MSH3):c.1148del (p.Lys383fs)
Variation ID: 8738 Accession: VCV000008738.25
- Type and length
-
Deletion, 1 bp
- Location
-
Cytogenetic: 5q14.1 5: 80675096 (GRCh38) [ NCBI UCSC ] 5: 79970915 (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 Dec 15, 2018 Mar 16, 2024 Jan 10, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_002439.5:c.1148del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002430.3:p.Lys383fs frameshift NM_002439.4:c.1148delA NC_000005.10:g.80675103del NC_000005.9:g.79970922del NG_016607.2:g.25629del NP_002430.3:p.Lys383Argfs - Protein change
- K383fs
- Other names
- -
- Canonical SPDI
- NC_000005.10:80675095:AAAAAAAA:AAAAAAA
-
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.
-
- Comment on variant
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. |
|||
MSH3 | - | - |
GRCh38 GRCh37 |
3821 | 4479 |
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 (2) |
criteria provided, single submitter
|
Aug 29, 2023 | RCV000009277.18 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 25, 2023 | RCV000240050.12 | |
Pathogenic (1) |
criteria provided, single submitter
|
Sep 14, 2022 | RCV001017472.10 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 10, 2024 | RCV000822053.20 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Dec 12, 2023 | RCV003944809.1 |
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
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. |
|
---|---|---|---|---|---|
Pathogenic
(Sep 14, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV001178556.3
First in ClinVar: Mar 16, 2020 Last updated: Nov 29, 2022 |
Comment:
The c.1148delA pathogenic mutation, located in coding exon 7 of the MSH3 gene, results from a deletion of one nucleotide at nucleotide position 1148, causing … (more)
The c.1148delA pathogenic mutation, located in coding exon 7 of the MSH3 gene, results from a deletion of one nucleotide at nucleotide position 1148, causing a translational frameshift with a predicted alternate stop codon (p.K383Rfs*32). This mutation was reported along with another MSH3 pathogenic mutation in two sisters: one diagnosed with colorectal cancer, colon polyps and gastric cancer, and the other with colon and duodenal polyps, thyroid adenoma and intraductal papillomas. Both parents were unaffected (Adam R et al. Am. J. Hum. Genet., 2016 Aug;99:337-51). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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)
Number of individuals with the variant: 1
|
|
Pathogenic
(Aug 29, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial adenomatous polyposis 4
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004189047.1
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.
|
|
Pathogenic
(Aug 21, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001471704.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
Comment:
The MSH3 c.1148delA; p.Lys383Argfs*32 variant (rs587776701) has been previously published with a additional pathogenic variant on the opposite chromosome in an individual with autosomal recessive … (more)
The MSH3 c.1148delA; p.Lys383Argfs*32 variant (rs587776701) has been previously published with a additional pathogenic variant on the opposite chromosome in an individual with autosomal recessive subtype4 of colorectal adenomatous polyposis (Adam 2016). The variant is reported as pathogenic in the ClinVar database (Variation ID: 8738) and is found in the general population with an overall allele frequency of 0.001079% (3/277,990 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Adam et al. Exome Sequencing Identifies Biallelic MSH3 Germline Mutations as a Recessive Subtype of Colorectal Adenomatous Polyposis. Am J Hum Genet. 2016 Aug 4;99(2):337-51. (less)
|
|
Pathogenic
(Feb 12, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Endometrial carcinoma
Affected status: unknown
Allele origin:
somatic
|
Centogene AG - the Rare Disease Company
Accession: SCV002028331.1
First in ClinVar: Dec 04, 2021 Last updated: Dec 04, 2021 |
|
|
Likely pathogenic
(Apr 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002818087.2
First in ClinVar: Jan 07, 2023 Last updated: Apr 23, 2023 |
Comment:
Observed with a second MSH3 variant in two siblings with multiple colorectal polyps, colorectal cancer, and other cancers (Adam et al., 2016); Frameshift variant predicted … (more)
Observed with a second MSH3 variant in two siblings with multiple colorectal polyps, colorectal cancer, and other cancers (Adam et al., 2016); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34843512, 27476653, 28528517, 8782829) (less)
|
|
Pathogenic
(Jan 25, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Endometrial carcinoma
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004197483.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
Pathogenic
(Jan 10, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000962837.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Lys383Argfs*32) in the MSH3 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Lys383Argfs*32) in the MSH3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH3 are known to be pathogenic (PMID: 27476653, 37402566). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with colorectal adenomatous polyposis (PMID: 27476653). ClinVar contains an entry for this variant (Variation ID: 8738). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Likely pathogenic
(Dec 12, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
MSH3-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004766293.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The MSH3 c.1148delA variant is predicted to result in a frameshift and premature protein termination (p.Lys383Argfs*32). This variant has been reported to be pathogenic in … (more)
The MSH3 c.1148delA variant is predicted to result in a frameshift and premature protein termination (p.Lys383Argfs*32). This variant has been reported to be pathogenic in a patient with autosomal recessive colorectal adenomatous polyposis (Adam et al. 2016. PubMed ID: 27476653). This variant is reported in 0.024% of alleles in individuals of European (Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/642843/). Frameshift variants in MSH3 are expected to be pathogenic. This variant is interpreted as likely pathogenic. (less)
|
|
Pathogenic
(Sep 01, 1996)
|
no assertion criteria provided
Method: literature only
|
FAMILIAL ADENOMATOUS POLYPOSIS 4
Affected status: not provided
Allele origin:
unknown
|
OMIM
Accession: SCV000029495.4
First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2018 |
Comment on evidence:
Familial Adenomatous Polyposis 4 In 2 sisters (family 1275) with autosomal recessive familial adenomatous polyposis-4 (FAP4; 617100), Adam et al. (2016) identified compound heterozygous mutations … (more)
Familial Adenomatous Polyposis 4 In 2 sisters (family 1275) with autosomal recessive familial adenomatous polyposis-4 (FAP4; 617100), Adam et al. (2016) identified compound heterozygous mutations in the MSH3 gene: a 1-bp deletion (c.1148delA, NM_002439.4) in exon 7, resulting in a frameshift and premature termination (Lys383ArgfsTer32), and an A-to-C transversion in intron 21 (c.3001-2A-C; 600887.0002), resulting in aberrant splicing and premature termination (Val1001ArgfsTer16) that would alter the dimerization domain. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were filtered against the dbSNP, 1000 Genomes Project, Exome Variant Server, and ExAC databases, and an in-house database of 2,816 control exomes. The c.1148delA mutation was found at a low frequency (0.008%) in the ExAC database. Endocrine Cancer, Somatic In a primary endometrial cancer (608089) and in an endometrial carcinoma cell line, Risinger et al. (1996) found a somatic mutation in the MSH3 gene. The mutation resulted in a truncated product and consisted of a single nucleotide deletion, loss of an A/T basepair at position 1148. This change generated a premature nonsense codon and results in a protein 723 amino acids shorter than the wildtype gene product. No wildtype DNA sequence or gene product was evident in the cell line. Residual wildtype sequence in protein was present in the primary tumor sample, which may have resulted from contaminating normal cells. The mutation was absent in the DNA of normal cells from the patient. (less)
|
|
Pathogenic
(Sep 01, 1996)
|
no assertion criteria provided
Method: literature only
|
ENDOMETRIAL CANCER, SOMATIC
Affected status: not provided
Allele origin:
somatic
|
OMIM
Accession: SCV000298243.2
First in ClinVar: Sep 04, 2016 Last updated: Dec 15, 2018 |
Comment on evidence:
Familial Adenomatous Polyposis 4 In 2 sisters (family 1275) with autosomal recessive familial adenomatous polyposis-4 (FAP4; 617100), Adam et al. (2016) identified compound heterozygous mutations … (more)
Familial Adenomatous Polyposis 4 In 2 sisters (family 1275) with autosomal recessive familial adenomatous polyposis-4 (FAP4; 617100), Adam et al. (2016) identified compound heterozygous mutations in the MSH3 gene: a 1-bp deletion (c.1148delA, NM_002439.4) in exon 7, resulting in a frameshift and premature termination (Lys383ArgfsTer32), and an A-to-C transversion in intron 21 (c.3001-2A-C; 600887.0002), resulting in aberrant splicing and premature termination (Val1001ArgfsTer16) that would alter the dimerization domain. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were filtered against the dbSNP, 1000 Genomes Project, Exome Variant Server, and ExAC databases, and an in-house database of 2,816 control exomes. The c.1148delA mutation was found at a low frequency (0.008%) in the ExAC database. Endocrine Cancer, Somatic In a primary endometrial cancer (608089) and in an endometrial carcinoma cell line, Risinger et al. (1996) found a somatic mutation in the MSH3 gene. The mutation resulted in a truncated product and consisted of a single nucleotide deletion, loss of an A/T basepair at position 1148. This change generated a premature nonsense codon and results in a protein 723 amino acids shorter than the wildtype gene product. No wildtype DNA sequence or gene product was evident in the cell line. Residual wildtype sequence in protein was present in the primary tumor sample, which may have resulted from contaminating normal cells. The mutation was absent in the DNA of normal cells from the patient. (less)
|
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 |
---|---|---|---|---|
MSH3: a confirmed predisposing gene for adenomatous polyposis. | Villy MC | Journal of medical genetics | 2023 | PMID: 37402566 |
Exome Sequencing Identifies Biallelic MSH3 Germline Mutations as a Recessive Subtype of Colorectal Adenomatous Polyposis. | Adam R | American journal of human genetics | 2016 | PMID: 27476653 |
Mutation of MSH3 in endometrial cancer and evidence for its functional role in heteroduplex repair. | Risinger JI | Nature genetics | 1996 | PMID: 8782829 |
Text-mined citations for rs587776701 ...
HelpRecord last updated Apr 20, 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.
NCBI staff reviewed the sequence information reported in PubMed 8782829 Fig. 1 to determine the location of this allele on the current reference sequence.