Multifactorial likelihood analysis posterior probability >0.99
ClinVar Genomic variation as it relates to human health
NM_000251.3(MSH2):c.1786_1788del (p.Asn596del)
Germline
Reviewed by expert panel
Help
Reviewed by expert panel. Learn more about how ClinVar calculates review status.
Pathogenic
for
Lynch Syndrome
Classification is based on the expert panel submission
Sep 2013 by
International Society for Gastrointestinal Hereditary Tumou…
Help
The classification is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000251.3(MSH2):c.1786_1788del (p.Asn596del)
Variation ID: 1757 Accession: VCV000001757.42
- Type and length
-
Deletion, 3 bp
- Location
-
Cytogenetic: 2p21 2: 47475051-47475053 (GRCh38) [ NCBI UCSC ] 2: 47702190-47702192 (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 Apr 4, 2013 Jan 3, 2026 Sep 5, 2013 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000251.3:c.1786_1788del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000242.1:p.Asn596del inframe deletion NM_000251.3:c.1786_1788delAAT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000251.1:c.1786_1788delAAT NM_000251.2:c.1786_1788delAAT NM_001258281.1:c.1588_1590del NP_001245210.1:p.Asn530del inframe deletion NC_000002.12:g.47475051_47475053del NC_000002.11:g.47702190_47702192del NG_007110.2:g.76928_76930del LRG_218:g.76928_76930del - Protein change
- N596del, N530del
- Other names
-
MSH2, 3-BP DEL, ASN596DEL
- Canonical SPDI
- NC_000002.12:47475050:AAT:
-
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.
-
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
- 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. |
|||
| MSH2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
8189 | 8394 | |
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 (6) |
criteria provided, multiple submitters, no conflicts
|
Dec 19, 2024 | RCV000001827.14 | |
| Pathogenic (3) |
reviewed by expert panel
|
Sep 5, 2013 | RCV000076285.9 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
May 26, 2025 | RCV000128908.14 | |
| Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Dec 29, 2025 | RCV000202293.16 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 23, 2025 | RCV000524362.11 | |
| Pathogenic (1) |
no assertion criteria provided
|
- | RCV001353543.1 | |
|
MSH2-related disorder
|
Pathogenic (1) |
criteria provided, single submitter
|
May 1, 2024 | RCV004797748.1 |
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. |
Expand all rows
Collapse all rows
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 05, 2013)
C
Contributing to aggregate classification
|
reviewed by expert panel
|
Lynch Syndrome |
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
Accession: SCV000107306.3
First in ClinVar: Dec 19, 2013 Last updated: Dec 24, 2022
Comment:
Classified with v1.9 guidelines: https://docs.google.com/file/d/0B3JL6rP6JzhoN2EydHRVMEI1UGs
|
Observation: 1
Collection method: research
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: research
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Jul 12, 2018)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Lynch syndrome |
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000919714.1
First in ClinVar: Jun 03, 2019 Last updated: Jun 03, 2019 |
Comment:
show
Variant summary: MSH2 c.1786_1788delAAT (p.Asn596del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 4.1e-06 in 246242 control chromosomes (gnomAD). The variant, c.1786_1788delAAT, has been reported in the literature in multiple individuals affected with Lynch Syndrome (Moslein_1996, Katballe_2002, Bonadona_2011, Stormorken_2005, Sunga_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Heinen_2003, Drost_2011, Heinen_2002). The most pronounced variant effect results in <10% of normal activity (Stormorken_2005). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Dec 18, 2014)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001450130.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 5
|
|
|
Pathogenic
(Jan 08, 2024)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Lynch syndrome
(Autosomal dominant inheritance)
|
All of Us Research Program, National Institutes of Health
Accession: SCV004827333.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
|
Comment:
show
This variant causes the in-frame deletion of asparagine 596 in the MSH3/MSH6 interaction and lever domains of the MSH2 protein. Functional studies have found the variant protein to be defective in DNA mismatch repair, ATP binding and ATPase assays (PMID: 12124176, 22102614). This variant has been observed in multiple individuals and families affected with colorectal cancer with DNA mismatch repair-deficient tumors or Lynch syndrome (PMID: 8592341, 8574961, 12436451, 16181381, 16807412, 21642682, 28874130, 28687971) and has been reported to segregate with disease (PMID: 11772966, 14574162, 15680406, 19723918, 20587412). This variant has been identified in 1/251458 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Number of individuals with the variant: 1
Zygosity: Single Heterozygote
|
|
|
Pathogenic
(May 01, 2024)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
MSH2-related disorder
|
Swedish National ChiCaP Initative, Genomic Medicine Sweden
Accession: SCV005419208.1
First in ClinVar: Dec 07, 2024 Last updated: Dec 07, 2024 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Jan 23, 2025)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Hereditary nonpolyposis colorectal neoplasms |
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000255273.13
First in ClinVar: Oct 11, 2015 Last updated: Feb 25, 2025 |
Comment:
show
This variant, c.1786_1788del, results in the deletion of 1 amino acid(s) of the MSH2 protein (p.Asn596del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs63749831, gnomAD 0.0009%). This variant has been observed in individual(s) with Lynch syndrome (PMID: 7874129, 8574961, 11772966, 14574162, 15680406, 17505997, 20587412, 21642682). It has also been observed to segregate with disease in related individuals. Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this MSH2 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for MSH2 testing. This variant is also known as Asn596del or N596del. ClinVar contains an entry for this variant (Variation ID: 1757). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects MSH2 function (PMID: 12124176, 22102614). For these reasons, this variant has been classified as Pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Nov 09, 2023)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Hereditary cancer-predisposing syndrome |
Color Diagnostics, LLC DBA Color Health
Accession: SCV000684976.4
First in ClinVar: Feb 19, 2018 Last updated: May 03, 2025 |
Comment:
show
This variant causes the in-frame deletion of asparagine 596 in the MSH3/MSH6 interaction and lever domains of the MSH2 protein. Functional studies have found the variant protein to be defective in DNA mismatch repair, ATP binding and ATPase assays (PMID: 12124176, 22102614). This variant has been observed in multiple individuals and families affected with Lynch syndrome or Lynch syndrome-associated cancer (PMID: 12436451, 14574162, 15680406, 16807412, 20587412, 21642682, 28874130, 28687971). The variant has been reported to segregate with disease (PMID: 14574162, 15680406, 20587412) This variant has been identified in 1/251458 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Platform type: NGS
|
|
|
Pathogenic
(Mar 15, 2021)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Not Provided |
GeneDx
Accession: SCV000211230.10
First in ClinVar: Feb 24, 2015 Last updated: Dec 19, 2017 |
Comment:
show
Observed in individuals with Lynch syndrome-related tumors, many with tumor studies demonstrating microsatellite instability (MSI-H) and lack of MSH2 protein expression, and segregating with disease in some families (Liu 1996, Katballe 2002, Wahlberg 2002, Stormorken 2003, Ripa 2005, Barnetson 2006, Pedroni 2007, Christensen 2008, Mueller 2009, Sjursen 2010, De Lellis 2013, Chubb 2015, DeRycke 2017, Rashid 2019, Cremin 2020, Wischhusen 2020); Published functional studies support a damaging effect: reduced DNA mispair recognition, binding, and ATP hydrolysis, and causing deficient mismatch repair activity (Heinen 2002, Drost 2012); In-frame deletion of 1 amino acid in a non-repeat region; Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 8574961, 10422993, 28874130, 28687971, 17594722, 24689082, 7874129, 14635101, 18566915, 25648859, 24307375, 25117503, 20007843, 23206658, 25345868, 21879275, 26177554, 19931546, 24362816, 22102614, 15680406, 25559809, 24278394, 21642682, 20587412, 26681312, 19690142, 23588873, 9774676, 14574162, 18561205, 16395668, 12436451, 11772966, 12067992, 16807412, 17473388, 21387278, 16181381, 17505997, 19723918, 21056691, 12124176, 18547406, 27601186, 28944238, 28596308, 28449805, 31660093, 32255556, 31615790) (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Mar 26, 2024)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Lynch syndrome 1 |
Baylor Genetics
Accession: SCV004196183.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
|
Pathogenic
(Dec 19, 2024)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Lynch syndrome 1 |
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre
Accession: SCV005442194.1
First in ClinVar: Jan 04, 2025 Last updated: Jan 04, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
pathogenic
(Oct 10, 2024)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001469802.3
First in ClinVar: Jan 26, 2021 Last updated: Jan 19, 2025 |
Comment:
show
The MSH2 c.1786_1788del (p.Asn596del) variant (Also known as Asn596del or N596del) has been reported in the published literature in multiple individuals/families with Lynch syndrome or Lynch-related conditions (PMIDs: 10995807 (2000), 14574162 (2003), 16181381 (2005), 17473388 (2007), 20587412 (2010), 28874130 (2017), 28640387 (2017), 28687971 (2018), 34178123 (2021), 34326862 (2021) and 38355628 (2024)). It has also been described as a founder mutation in the Danish population (PMIDs: 19931546 (2010) and 15680406 (2005)). Tumor analysis of the affected carries of this variant frequently showed immunohistochemical loss of MSH2 and high microsatellite instability (PMIDs: 14574162 (2003), 16181381 (2005), 17473388 (2007) and 34178123 (2021)). Also, in vitro studies indicated that the variant results in defective DNA repair, ATP binding and ATPase assay (PMIDs: 12124176 (2002), 22102614 (2012)). The frequency of this variant in the general population, 0.000004 (1/251458 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
|
Pathogenic
(May 26, 2025)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Hereditary cancer-predisposing syndrome |
Ambry Genetics
Accession: SCV000172775.10
First in ClinVar: Aug 06, 2014 Last updated: Jul 13, 2025 |
Comment:
show
The c.1786_1788delAAT pathogenic mutation (also known as p.N596del) is located in coding exon 12 of the MSH2 gene. This mutation results from the deletion of three nucleotides (AAT) at nucleotide positions 1786 to 1788, resulting in the in-frame deletion of a well-conserved asparagine residue at codon 596. The deleted asparagine residue is positioned just upstream from the conserved C-terminal domain, shown by in vitro studies to bind mismatched oligonucleotides and to hold ATPase activity. This domain is important for the function of the MSH2 protein in vivo (Whitehouse et al. Biochem Biophys Res Comm. 1997. 232: 10-13; Heinen et al. Cancer Cell 2002 Jun; 1(5): 469-78). This alteration has been detected in numerous individuals with HNPCC/Lynch syndrome and has segregated with disease in several families (Ripa et al. Mutat Res 2005 Feb 15; 570(1): 89-96; Stormorken et al. Fam Cancer 2003; 2(1): 9-13; Buerstedde J et al. J Med Genet. 1995;35:909-12; Mary J et al. Hum Mol Genet. 1994:3:2067-9; Dunlop M et al. Hum Mol Genet. 1997;6:105-10; Liu B et al. Nat Med. 1996;2:169-74; Moslein G et al. Hum Mol Genet. 1996;5:1245-52; Sjursen W et al. J. Med. Genet. 2010 Sep;47(9):579-85; Limburg PJ et al. Clin. Gastroenterol. Hepatol., 2011 Jun;9:497-502; Rossi BM et al. BMC Cancer, 2017 Sep;17:623). In addition, immunohistochemical (IHC) analysis performed on tumors from affected carriers in these studies has frequently revealed absent MSH2 and MSH6 staining. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Dec 29, 2025)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV004243562.3
First in ClinVar: Feb 14, 2024 Last updated: Jan 03, 2026 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Mar 24, 2023)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Lynch syndrome 1 |
Myriad Genetics, Inc.
Accession: SCV004018427.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
show
This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 14574162, 15680406]. (less)
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
|
Pathogenic
(May 27, 2022)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005197464.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
not provided |
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000257152.2
First in ClinVar: Nov 20, 2015 Last updated: Dec 19, 2017 |
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Carcinoma of colon |
Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV000592519.2 First in ClinVar: Oct 11, 2015 Last updated: Apr 13, 2021 |
Comment:
show
The p.Asn596del deletion has been previously reported in the literature in over 35 proband chromosomes in individuals with HNPCC (Selected publications: Auclair 2006, Barnetson 2006, Bisgaard 2002, Guerrette 1998, Heinen 2002, Grindedal 2009, Irmejs 2007, Stormorken 2003, Tournier 2008, Wahlberg 2002, Ripa 2005). This variant results in an in-frame deletion and removal of amino acid residue p.Asn596. At least two studies examined large kindreds and the mutation was linked to the disease with LOD scores of 5.7, 3.2 and 2, respectively, strongly supporting a pathogenic role for this deletion (Stormorken 2003, Ripa 2005). In addition, several studies have demonstrated MSH2 immunohistochemistry deficiency or MSI-high tumors in individuals with this deletion (Stormorken 2003, Losi 2005, Pedroni 2007) increasing the likelihood this variant is pathogenic. In summary, based on the above information, this variant is classified as pathogenic. (less)
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
Number of individuals with the variant: 5
|
|
|
Pathogenic
(Nov 01, 1994)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
LYNCH SYNDROME 1 |
OMIM
Accession: SCV000021983.2
First in ClinVar: Apr 04, 2013 Last updated: Jun 09, 2024 |
Observation: 1
Collection method: literature only
Allele origin: germline
Affected status: not provided
Observation 1
Collection method: literature only
Allele origin: germline
Affected status: not provided
Comment on evidence:
In a family in which 3 first-degree relatives developed colon cancer (LYNCH1; 120435) under the age of 45 years, with all neoplasms being mucinous adenocarcinomas, … (more)
In a family in which 3 first-degree relatives developed colon cancer (LYNCH1; 120435) under the age of 45 years, with all neoplasms being mucinous adenocarcinomas, Mary et al. (1994) found deletion of codon 596 (AAT) resulting in the deletion of an asparagine residue from the protein. (less)
|
|
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Pathogenic
(Nov 11, 2016)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Lynch syndrome 1 |
Counsyl
Accession: SCV000489696.3
First in ClinVar: Oct 22, 2016 Last updated: Jun 29, 2025 |
Comment:
show
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. (less)
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
|
not provided
(-)
N
Not contributing to aggregate classification
|
no classification provided
|
Lynch syndrome 1 |
GeneReviews
Accession: SCV002054072.2
First in ClinVar: Jan 08, 2022 Last updated: Oct 01, 2022 |
Observation: 1
Collection method: literature only
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: literature only
Allele origin: germline
Affected status: unknown
|
|
Comment:
Comment:
Variant summary: MSH2 c.1786_1788delAAT (p.Asn596del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 4.1e-06 in 246242 control chromosomes (gnomAD). The variant, c.1786_1788delAAT, has been reported in the literature in multiple individuals affected with Lynch Syndrome (Moslein_1996, Katballe_2002, Bonadona_2011, Stormorken_2005, Sunga_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Heinen_2003, Drost_2011, Heinen_2002). The most pronounced variant effect results in <10% of normal activity (Stormorken_2005). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This variant causes the in-frame deletion of asparagine 596 in the MSH3/MSH6 interaction and lever domains of the MSH2 protein. Functional studies have found the variant protein to be defective in DNA mismatch repair, ATP binding and ATPase assays (PMID: 12124176, 22102614). This variant has been observed in multiple individuals and families affected with colorectal cancer with DNA mismatch repair-deficient tumors or Lynch syndrome (PMID: 8592341, 8574961, 12436451, 16181381, 16807412, 21642682, 28874130, 28687971) and has been reported to segregate with disease (PMID: 11772966, 14574162, 15680406, 19723918, 20587412). This variant has been identified in 1/251458 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
This variant, c.1786_1788del, results in the deletion of 1 amino acid(s) of the MSH2 protein (p.Asn596del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs63749831, gnomAD 0.0009%). This variant has been observed in individual(s) with Lynch syndrome (PMID: 7874129, 8574961, 11772966, 14574162, 15680406, 17505997, 20587412, 21642682). It has also been observed to segregate with disease in related individuals. Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this MSH2 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for MSH2 testing. This variant is also known as Asn596del or N596del. ClinVar contains an entry for this variant (Variation ID: 1757). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects MSH2 function (PMID: 12124176, 22102614). For these reasons, this variant has been classified as Pathogenic.
Comment:
This variant causes the in-frame deletion of asparagine 596 in the MSH3/MSH6 interaction and lever domains of the MSH2 protein. Functional studies have found the variant protein to be defective in DNA mismatch repair, ATP binding and ATPase assays (PMID: 12124176, 22102614). This variant has been observed in multiple individuals and families affected with Lynch syndrome or Lynch syndrome-associated cancer (PMID: 12436451, 14574162, 15680406, 16807412, 20587412, 21642682, 28874130, 28687971). The variant has been reported to segregate with disease (PMID: 14574162, 15680406, 20587412) This variant has been identified in 1/251458 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
Observed in individuals with Lynch syndrome-related tumors, many with tumor studies demonstrating microsatellite instability (MSI-H) and lack of MSH2 protein expression, and segregating with disease in some families (Liu 1996, Katballe 2002, Wahlberg 2002, Stormorken 2003, Ripa 2005, Barnetson 2006, Pedroni 2007, Christensen 2008, Mueller 2009, Sjursen 2010, De Lellis 2013, Chubb 2015, DeRycke 2017, Rashid 2019, Cremin 2020, Wischhusen 2020); Published functional studies support a damaging effect: reduced DNA mispair recognition, binding, and ATP hydrolysis, and causing deficient mismatch repair activity (Heinen 2002, Drost 2012); In-frame deletion of 1 amino acid in a non-repeat region; Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 8574961, 10422993, 28874130, 28687971, 17594722, 24689082, 7874129, 14635101, 18566915, 25648859, 24307375, 25117503, 20007843, 23206658, 25345868, 21879275, 26177554, 19931546, 24362816, 22102614, 15680406, 25559809, 24278394, 21642682, 20587412, 26681312, 19690142, 23588873, 9774676, 14574162, 18561205, 16395668, 12436451, 11772966, 12067992, 16807412, 17473388, 21387278, 16181381, 17505997, 19723918, 21056691, 12124176, 18547406, 27601186, 28944238, 28596308, 28449805, 31660093, 32255556, 31615790)
Comment:
The MSH2 c.1786_1788del (p.Asn596del) variant (Also known as Asn596del or N596del) has been reported in the published literature in multiple individuals/families with Lynch syndrome or Lynch-related conditions (PMIDs: 10995807 (2000), 14574162 (2003), 16181381 (2005), 17473388 (2007), 20587412 (2010), 28874130 (2017), 28640387 (2017), 28687971 (2018), 34178123 (2021), 34326862 (2021) and 38355628 (2024)). It has also been described as a founder mutation in the Danish population (PMIDs: 19931546 (2010) and 15680406 (2005)). Tumor analysis of the affected carries of this variant frequently showed immunohistochemical loss of MSH2 and high microsatellite instability (PMIDs: 14574162 (2003), 16181381 (2005), 17473388 (2007) and 34178123 (2021)). Also, in vitro studies indicated that the variant results in defective DNA repair, ATP binding and ATPase assay (PMIDs: 12124176 (2002), 22102614 (2012)). The frequency of this variant in the general population, 0.000004 (1/251458 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Comment:
The c.1786_1788delAAT pathogenic mutation (also known as p.N596del) is located in coding exon 12 of the MSH2 gene. This mutation results from the deletion of three nucleotides (AAT) at nucleotide positions 1786 to 1788, resulting in the in-frame deletion of a well-conserved asparagine residue at codon 596. The deleted asparagine residue is positioned just upstream from the conserved C-terminal domain, shown by in vitro studies to bind mismatched oligonucleotides and to hold ATPase activity. This domain is important for the function of the MSH2 protein in vivo (Whitehouse et al. Biochem Biophys Res Comm. 1997. 232: 10-13; Heinen et al. Cancer Cell 2002 Jun; 1(5): 469-78). This alteration has been detected in numerous individuals with HNPCC/Lynch syndrome and has segregated with disease in several families (Ripa et al. Mutat Res 2005 Feb 15; 570(1): 89-96; Stormorken et al. Fam Cancer 2003; 2(1): 9-13; Buerstedde J et al. J Med Genet. 1995;35:909-12; Mary J et al. Hum Mol Genet. 1994:3:2067-9; Dunlop M et al. Hum Mol Genet. 1997;6:105-10; Liu B et al. Nat Med. 1996;2:169-74; Moslein G et al. Hum Mol Genet. 1996;5:1245-52; Sjursen W et al. J. Med. Genet. 2010 Sep;47(9):579-85; Limburg PJ et al. Clin. Gastroenterol. Hepatol., 2011 Jun;9:497-502; Rossi BM et al. BMC Cancer, 2017 Sep;17:623). In addition, immunohistochemical (IHC) analysis performed on tumors from affected carriers in these studies has frequently revealed absent MSH2 and MSH6 staining. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 14574162, 15680406].
Comment:
The p.Asn596del deletion has been previously reported in the literature in over 35 proband chromosomes in individuals with HNPCC (Selected publications: Auclair 2006, Barnetson 2006, Bisgaard 2002, Guerrette 1998, Heinen 2002, Grindedal 2009, Irmejs 2007, Stormorken 2003, Tournier 2008, Wahlberg 2002, Ripa 2005). This variant results in an in-frame deletion and removal of amino acid residue p.Asn596. At least two studies examined large kindreds and the mutation was linked to the disease with LOD scores of 5.7, 3.2 and 2, respectively, strongly supporting a pathogenic role for this deletion (Stormorken 2003, Ripa 2005). In addition, several studies have demonstrated MSH2 immunohistochemistry deficiency or MSI-high tumors in individuals with this deletion (Stormorken 2003, Losi 2005, Pedroni 2007) increasing the likelihood this variant is pathogenic. In summary, based on the above information, this variant is classified as pathogenic.
Comment:
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Germline mutations of 4567 patients with hereditary breast-ovarian cancer spectrum in Thailand. | Kansuttiviwat C | NPJ genomic medicine | 2024 | PMID: 38355628 |
| Merged testing for colorectal cancer syndromes and re-evaluation of genetic variants improve diagnostic yield: Results from a nationwide prospective cohort. | Svensson S | Genes, chromosomes & cancer | 2022 | PMID: 35430768 |
| Analysis of Sequence and Copy Number Variants in Canadian Patient Cohort With Familial Cancer Syndromes Using a Unique Next Generation Sequencing Based Approach. | Bhai P | Frontiers in genetics | 2021 | PMID: 34326862 |
| Development and external validation of a novel nomogram for screening Chinese Lynch syndrome: based on a multicenter, population study. | Yang M | Therapeutic advances in medical oncology | 2021 | PMID: 34178123 |
| Germline mutations and age at onset of lung adenocarcinoma. | Reckamp KL | Cancer | 2021 | PMID: 33858029 |
| Lynch Syndrome. | Adam MP | - | 2021 | PMID: 20301390 |
| The spectrum of genetic variants in hereditary pancreatic cancer includes Fanconi anemia genes. | Slavin TP | Familial cancer | 2018 | PMID: 28687971 |
| A survey of the clinicopathological and molecular characteristics of patients with suspected Lynch syndrome in Latin America. | Rossi BM | BMC cancer | 2017 | PMID: 28874130 |
| DNA mismatch repair deficiency and hereditary syndromes in Latino patients with colorectal cancer. | Ricker CN | Cancer | 2017 | PMID: 28640387 |
| Spectrum of mismatch repair gene mutations and clinical presentation of Hispanic individuals with Lynch syndrome. | Sunga AY | Cancer genetics | 2017 | PMID: 28449805 |
| A massive parallel sequencing workflow for diagnostic genetic testing of mismatch repair genes. | Hansen MF | Molecular genetics & genomic medicine | 2014 | PMID: 24689082 |
| 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 |
| A rapid and cell-free assay to test the activity of lynch syndrome-associated MSH2 and MSH6 missense variants. | Drost M | Human mutation | 2012 | PMID: 22102614 |
| Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. | Bonadona V | JAMA | 2011 | PMID: 21642682 |
| Prevalence of alterations in DNA mismatch repair genes in patients with young-onset colorectal cancer. | Limburg PJ | Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association | 2011 | PMID: 21056691 |
| Current clinical criteria for Lynch syndrome are not sensitive enough to identify MSH6 mutation carriers. | Sjursen W | Journal of medical genetics | 2010 | PMID: 20587412 |
| Detection of genetic alterations in hereditary colorectal cancer screening. | Pineda M | Mutation research | 2010 | PMID: 19931546 |
| Germ-line mutations in mismatch repair genes associated with prostate cancer. | Grindedal EM | Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology | 2009 | PMID: 19723918 |
| Genotype-phenotype correlations in individuals with a founder mutation in the MLH1 gene and hereditary non-polyposis colorectal cancer. | de Leon MP | Scandinavian journal of gastroenterology | 2007 | PMID: 17505997 |
| A mononucleotide markers panel to identify hMLH1/hMSH2 germline mutations. | Pedroni M | Disease markers | 2007 | PMID: 17473388 |
| Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer. | Barnetson RA | The New England journal of medicine | 2006 | PMID: 16807412 |
| Molecular genetic alterations and clinical features in early-onset colorectal carcinomas and their role for the recognition of hereditary cancer syndromes. | Losi L | The American journal of gastroenterology | 2005 | PMID: 16181381 |
| Immunohistochemistry identifies carriers of mismatch repair gene defects causing hereditary nonpolyposis colorectal cancer. | Stormorken AT | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2005 | PMID: 16034045 |
| Presymptomatic diagnosis using a deletion of a single codon in families with hereditary non-polyposis colorectal cancer. | Ripa RS | Mutation research | 2005 | PMID: 15680406 |
| The inframe MSH2 codon 596 deletion is linked with HNPCC and associated with lack of MSH2 protein in tumours. | Stormorken AT | Familial cancer | 2003 | PMID: 14574162 |
| Antibody-based screening for hereditary nonpolyposis colorectal carcinoma compared with microsatellite analysis and sequencing. | Christensen M | Cancer | 2002 | PMID: 12436451 |
| HNPCC mutations in hMSH2 result in reduced hMSH2-hMSH6 molecular switch functions. | Heinen CD | Cancer cell | 2002 | PMID: 12124176 |
| Frequency of hereditary non-polyposis colorectal cancer in Danish colorectal cancer patients. | Katballe N | Gut | 2002 | PMID: 11772966 |
| Characterization of hereditary nonpolyposis colorectal cancer families from a population-based series of cases. | Peel DJ | Journal of the National Cancer Institute | 2000 | PMID: 10995807 |
| Mapping the minimal domain of hMSH-2 sufficient for binding mismatched oligonucleotides. | Whitehouse A | Biochemical and biophysical research communications | 1997 | PMID: 9125109 |
| Cancer risk associated with germline DNA mismatch repair gene mutations. | Dunlop MG | Human molecular genetics | 1997 | PMID: 9002677 |
| Microsatellite instability and mutation analysis of hMSH2 and hMLH1 in patients with sporadic, familial and hereditary colorectal cancer. | Moslein G | Human molecular genetics | 1996 | PMID: 8872463 |
| Analysis of mismatch repair genes in hereditary non-polyposis colorectal cancer patients. | Liu B | Nature medicine | 1996 | PMID: 8574961 |
| Detection of new mutations in six out of 10 Swiss HNPCC families by genomic sequencing of the hMSH2 and hMLH1 genes. | Buerstedde JM | Journal of medical genetics | 1995 | PMID: 8592341 |
| Mutational analysis of the hMSH2 gene reveals a three base pair deletion in a family predisposed to colorectal cancer development. | Mary JL | Human molecular genetics | 1994 | PMID: 7874129 |
| http://www.insight-database.org/classifications/index.html?gene=MSH2&variant=c.1786_1788del | - | - | - | - |
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Record last updated Jan 03, 2026
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.