ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.1786_1788del (p.Asn596del) (rs63749831)

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Total submissions: 10
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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 2019-03-15 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Good segregation with disease (lod 1.5-3 = 5-9 meioses);Deficient protein function in appropriate functional assay(s);Other strong data supporting pathogenic classification
GeneDx RCV000202293 SCV000211230 pathogenic not provided 2018-05-16 criteria provided, single submitter clinical testing This in-frame deletion of three nucleotides is denoted MSH2 c.1786_1788delAAT at the cDNA level and p.Asn596del (N596del) at the protein level. The normal sequence, with the bases that are deleted in brackets, is ACTC[delAAT]GATG. This variant has been identified in several individuals with a personal and/or family history of Lynch syndrome-related tumors, with tumor studies in many demonstrating microsatellite instability (MSI-H) and lack of MSH2 protein expression (Liu 1996, Katballe 2002, Wahlberg 2002, Barnetson 2006, Pedroni 2007, Christensen 2008, Mueller 2009, Sjursen 2010, De Lellis 2013, Chubb 2015, DeRycke 2017). In addition, MSH2 Asn596del has been shown to segregate with Lynch syndrome-associated cancers in several families (Stormorken 2003, Ripa 2005). While functional assays interrogating MSH6/MSH3 binding and splicing produced normal results (Guerrette 1998, Auclair 2006, Tournier 2008), other studies found this variant to reduce DNA mispair recognition and binding and ATP hydrolysis, and to ultimately cause deficient mismatch repair activity, suggesting pathogenicity (Heinen 2002, Drost 2012). Additionally, the International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as pathogenic based on their multifactorial likelihood analysis (Thompson 2014). MSH2 Asn596del was not observed at a significant allele frequency in large population cohorts (Lek 2016). This deletion of a single Asparagine residue is located within the Lever domain and the region of interaction with MSH6 and MSH3 (Guerrette 1998, Lutzen 2008, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider MSH2 Asn596del to be pathogenic.
Invitae RCV000524362 SCV000255273 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-10-19 criteria provided, single submitter clinical testing This sequence change deletes 3 nucleotides from exon 12 of the MSH2 mRNA (c.1786_1788delAAT). This leads to the deletion of 1 amino acid residue in the MSH2 protein (p.Asn596del) but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs63749831, ExAC 0.002%). This variant has been observed in many individuals with Lynch syndrome (PMID: 7874129, 15680406, 11772966, 20587412, 21642682, 17505997, 14574162, 8574961), and has been shown to segregate with disease in multiple families (PMID: 14574162, 7874129, 15680406, 11772966, 20587412). This variant is also known as Asn596del or N596del in the literature. ClinVar contains an entry for this variant (Variation ID: 1757). Experimental studies demonstrate that the Asn596del protein is functionally impaired, with reduced ability to dimerize with MSH6, reduced ability to bind G-T mismatch DNA, and deficiency in ADP to ATP exchange (PMID: 12124176). This variant is also reported to be deficient in mismatch repair activity (PMID: 22102614). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000001827 SCV000489696 pathogenic Lynch syndrome I 2016-11-11 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000076285 SCV000592519 pathogenic Lynch syndrome 2016-10-21 criteria provided, single submitter clinical testing
Color RCV000128908 SCV000684976 pathogenic Hereditary cancer-predisposing syndrome 2016-10-12 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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.
OMIM RCV000001827 SCV000021983 pathogenic Lynch syndrome I 1994-11-01 no assertion criteria provided literature only
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202293 SCV000257152 pathogenic not provided no assertion criteria provided clinical testing

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