The c.1697delA pathogenic mutation, located in coding exon 11 of the MSH2 gene, results from a deletion of one nucleotide at nucleotide position 1697, causing a translational frameshift with a predicted alternate stop codon (p.N566Ifs*24). This alteration has been reported in a patient with endometrial cancer, diagnosed at age 44, that demonstrated loss of MSH2 and MSH6 protein expression by immunohistochemistry (IHC) staining (Batte BA et al. Gynecol. Oncol., 2014 Aug;134:319-25). This alteration has also been reported in a child diagnosed with glioblastoma (Parsons DW et al. JAMA Oncol, 2016 May;2:616-624). 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_000251.3(MSH2):c.1697del (p.Asn566fs)
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.
(6)
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
6
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_000251.3(MSH2):c.1697del (p.Asn566fs)
Variation ID: 141147 Accession: VCV000141147.18
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 2p21 2: 47470996 (GRCh38) [ NCBI UCSC ] 2: 47698135 (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 Sep 24, 2016 May 1, 2024 Mar 5, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000251.3:c.1697del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000242.1:p.Asn566fs frameshift NM_000251.3:c.1697delA MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001258281.1:c.1499del NP_001245210.1:p.Asn500fs frameshift NC_000002.12:g.47471000del NC_000002.11:g.47698139del NG_007110.2:g.72877del LRG_218:g.72877del LRG_218t1:c.1697del LRG_218p1:p.Asn566fs - Protein change
- N500fs, N566fs
- Other names
- -
- Canonical SPDI
- NC_000002.12:47470995:AAAAA:AAAA
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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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| MSH2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
7404 | 7566 | |
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, multiple submitters, no conflicts
|
Mar 5, 2024 | RCV000129525.9 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 8, 2023 | RCV001235798.8 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Aug 3, 2023 | RCV003447499.3 |
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
(Nov 25, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome 1
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004196882.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
|
Pathogenic
(Mar 05, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000184301.9
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The c.1697delA pathogenic mutation, located in coding exon 11 of the MSH2 gene, results from a deletion of one nucleotide at nucleotide position 1697, causing … (more)
The c.1697delA pathogenic mutation, located in coding exon 11 of the MSH2 gene, results from a deletion of one nucleotide at nucleotide position 1697, causing a translational frameshift with a predicted alternate stop codon (p.N566Ifs*24). This alteration has been reported in a patient with endometrial cancer, diagnosed at age 44, that demonstrated loss of MSH2 and MSH6 protein expression by immunohistochemistry (IHC) staining (Batte BA et al. Gynecol. Oncol., 2014 Aug;134:319-25). This alteration has also been reported in a child diagnosed with glioblastoma (Parsons DW et al. JAMA Oncol, 2016 May;2:616-624). 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)
|
|
|
Pathogenic
(Nov 24, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004175693.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
Comment:
The MSH2 c.1697del variant is classified as Pathogenic (PVS1, PM2, PP4) This MSH2 c.1697del variant is located in exon 11/16 and is predicted to cause … (more)
The MSH2 c.1697del variant is classified as Pathogenic (PVS1, PM2, PP4) This MSH2 c.1697del variant is located in exon 11/16 and is predicted to cause a shift in the reading frame at codon 566. The variant has been reported in 3 probands with a clinical presentation of colorectal cancer (HGMD: CD1410481) (PS4_Moderate). This variant is absent from population databases (PM2). The clinical features of this case are highly specific for the MSH2 gene due to loss of expression of MSH2/MSH in IHC tumour staining (PP4). The variant has been reported in dbSNP (rs63750737) and in the HGMD database: CD1410481. It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 141147). (less)
|
|
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Pathogenic
(Nov 01, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV001354536.2
First in ClinVar: Jun 22, 2020 Last updated: Jan 12, 2022 |
Comment:
This variant deletes 1 nucleotide in exon 11 of the MSH2 gene, creating a frameshift and premature translation stop signal. This variant is expected to … (more)
This variant deletes 1 nucleotide in exon 11 of the MSH2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with endometrial cancer (PMID: 24933100). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. (less)
|
|
|
Pathogenic
(Aug 03, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Lynch syndrome 1
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004187965.1
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
(Sep 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary nonpolyposis colorectal neoplasms
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001408503.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Asn566Ilefs*24) in the MSH2 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Asn566Ilefs*24) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Lynch-related cancers (PMID: 24933100, 26822237, 31615790). ClinVar contains an entry for this variant (Variation ID: 141147). For these reasons, this variant has been classified as Pathogenic. (less)
|
Comment:
Comment:
The MSH2 c.1697del variant is classified as Pathogenic (PVS1, PM2, PP4) This MSH2 c.1697del variant is located in exon 11/16 and is predicted to cause a shift in the reading frame at codon 566. The variant has been reported in 3 probands with a clinical presentation of colorectal cancer (HGMD: CD1410481) (PS4_Moderate). This variant is absent from population databases (PM2). The clinical features of this case are highly specific for the MSH2 gene due to loss of expression of MSH2/MSH in IHC tumour staining (PP4). The variant has been reported in dbSNP (rs63750737) and in the HGMD database: CD1410481. It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 141147).
Comment:
This variant deletes 1 nucleotide in exon 11 of the MSH2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with endometrial cancer (PMID: 24933100). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic.
Comment:
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Comment:
This sequence change creates a premature translational stop signal (p.Asn566Ilefs*24) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Lynch-related cancers (PMID: 24933100, 26822237, 31615790). ClinVar contains an entry for this variant (Variation ID: 141147). For these reasons, this variant has been classified as 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.1697delA pathogenic mutation, located in coding exon 11 of the MSH2 gene, results from a deletion of one nucleotide at nucleotide position 1697, causing a translational frameshift with a predicted alternate stop codon (p.N566Ifs*24). This alteration has been reported in a patient with endometrial cancer, diagnosed at age 44, that demonstrated loss of MSH2 and MSH6 protein expression by immunohistochemistry (IHC) staining (Batte BA et al. Gynecol. Oncol., 2014 Aug;134:319-25). This alteration has also been reported in a child diagnosed with glioblastoma (Parsons DW et al. JAMA Oncol, 2016 May;2:616-624). 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:
The MSH2 c.1697del variant is classified as Pathogenic (PVS1, PM2, PP4) This MSH2 c.1697del variant is located in exon 11/16 and is predicted to cause a shift in the reading frame at codon 566. The variant has been reported in 3 probands with a clinical presentation of colorectal cancer (HGMD: CD1410481) (PS4_Moderate). This variant is absent from population databases (PM2). The clinical features of this case are highly specific for the MSH2 gene due to loss of expression of MSH2/MSH in IHC tumour staining (PP4). The variant has been reported in dbSNP (rs63750737) and in the HGMD database: CD1410481. It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 141147).
Comment:
This variant deletes 1 nucleotide in exon 11 of the MSH2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with endometrial cancer (PMID: 24933100). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic.
Comment:
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Comment:
This sequence change creates a premature translational stop signal (p.Asn566Ilefs*24) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Lynch-related cancers (PMID: 24933100, 26822237, 31615790). ClinVar contains an entry for this variant (Variation ID: 141147). For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Clinical Factors Associated with Urinary Tract Cancer in Individuals with Lynch Syndrome. | Wischhusen JW | Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology | 2020 | PMID: 31615790 |
| Diagnostic Yield of Clinical Tumor and Germline Whole-Exome Sequencing for Children With Solid Tumors. | Parsons DW | JAMA oncology | 2016 | PMID: 26822237 |
| Consequences of universal MSI/IHC in screening ENDOMETRIAL cancer patients for Lynch syndrome. | Batte BA | Gynecologic oncology | 2014 | PMID: 24933100 |
| Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database. | Thompson BA | Nature genetics | 2014 | PMID: 24362816 |
| Spectrum and frequencies of mutations in MSH2 and MLH1 identified in 1,721 German families suspected of hereditary nonpolyposis colorectal cancer. | Mangold E | International journal of cancer | 2005 | PMID: 15849733 |
Text-mined citations for rs63750737 ...
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 Sep 29, 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.