Submissions for variant NM_000251.3(MSH2):c.1786_1788del (p.Asn596del)

dbSNP: rs63749831

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076285	SCV000107306	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability >0.99
Ambry Genetics	RCV000128908	SCV000172775	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-24	criteria provided, single submitter	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.
GeneDx	RCV000202293	SCV000211230	pathogenic	not provided	2021-03-15	criteria provided, single submitter	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)
Invitae	RCV000524362	SCV000255273	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-22	criteria provided, single submitter	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. 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 protein 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.
Counsyl	RCV000001827	SCV000489696	pathogenic	Lynch syndrome 1	2016-11-11	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000128908	SCV000684976	pathogenic	Hereditary cancer-predisposing syndrome	2023-11-09	criteria provided, single submitter	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000076285	SCV000919714	pathogenic	Lynch syndrome	2018-07-12	criteria provided, single submitter	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.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000202293	SCV001450130	pathogenic	not provided	2014-12-18	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000202293	SCV001469802	pathogenic	not provided	2020-01-20	criteria provided, single submitter	clinical testing	The variant has been reported in individuals affected with colorectal and pancreatic cancers and is considered to be a founder mutation in the Danish population in the published literature (PMID: 10995807 (2000), 19931546 (2010), 28640387 (2017), 28687971 (2018), 28874130 (2017)). A functional study found that this variant showed decreased repair activity (PMID: 22102614 (2012)). Based on the available information, this variant is classified as pathogenic.
Myriad Genetics, Inc.	RCV000001827	SCV004018427	pathogenic	Lynch syndrome 1	2023-03-24	criteria provided, single submitter	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].
Baylor Genetics	RCV000001827	SCV004196183	pathogenic	Lynch syndrome 1	2023-10-17	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000202293	SCV004243562	pathogenic	not provided	2024-02-06	criteria provided, single submitter	clinical testing
OMIM	RCV000001827	SCV000021983	pathogenic	Lynch syndrome 1	1994-11-01	no assertion criteria provided	literature only
Mayo Clinic Laboratories, Mayo Clinic	RCV000202293	SCV000257152	pathogenic	not provided		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353543	SCV000592519	pathogenic	Carcinoma of colon		no assertion criteria provided	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.
GeneReviews	RCV000001827	SCV002054072	not provided	Lynch syndrome 1		no assertion provided	literature only