rs63749831

Variant names:

• chr2-47475050-CAAT-C
• rs63749831
• NM_000251.3:c.1786_1788delAAT

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_000251.3(MSH2):​c.1786_1788delAAT​(p.Asn596del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,262 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MSH2 NM_000251.3 conservative_inframe_deletion
• Clinical Significance: Pathogenic reviewed by expert panel P:19 O:1
• Conservation: PhyloP100: 8.51

Genes affected

MSH2 (HGNC:7325): (mutS homolog 2) This locus is frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). When cloned, it was discovered to be a human homolog of the E. coli mismatch repair gene mutS, consistent with the characteristic alterations in microsatellite sequences (RER+ phenotype) found in HNPCC. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM1: In a helix (size 24) in uniprot entity MSH2_HUMAN there are 10 pathogenic changes around while only 2 benign (83%) in NM_000251.3
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000251.3. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 2-47475050-CAAT-C is Pathogenic according to our data. Variant chr2-47475050-CAAT-C is described in ClinVar as [Pathogenic]. Clinvar id is 1757.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475050-CAAT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.1786_1788delAAT	p.Asn596del	conservative_inframe_deletion	Exon 12 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.1786_1788delAAT	p.Asn596del	conservative_inframe_deletion	Exon 12 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251458 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135896

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461262 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 726978

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:19 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:6

-

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 10, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 15, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 18, 2014

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome 1 Pathogenic:5 Other:1

Dec 19, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Mar 24, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 14574162, 15680406]. -

Mar 26, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 11, 2016

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 1994

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Lynch syndrome Pathogenic:3

Sep 05, 2013

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: research

Multifactorial likelihood analysis posterior probability >0.99 -

Jul 12, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 08, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Mar 24, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 09, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

MSH2-related disorder Pathogenic:1

May 01, 2024

Swedish National ChiCaP Initative, Genomic Medicine Sweden

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Carcinoma of colon Pathogenic:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs63749831; hg19: chr2-47702189;