Submissions for variant NM_000251.3(MSH2):c.568CTC[1] (p.Leu191del)

dbSNP: rs587779165

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076643	SCV000107678	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability >0.99
GeneDx	RCV000497286	SCV000211232	pathogenic	not provided	2023-12-28	criteria provided, single submitter	clinical testing	In-frame deletion of one amino acid in a non-repeat region; Observed in individuals with MSH2-related cancers, some of which demonstrated absence of MSH2 and/or MSH6 protein expression in tumors (PMID: 33003368, 20587412); Not observed at significant frequency in large population cohorts (gnomAD); Classified pathogenic by a well-established clinical consortium and/or database (InSiGHT); This variant is associated with the following publications: (PMID: 22949379, 24689082, 24362816, 26681312, 20587412, 19267393, 30787465, 18822302, 21120944, Tsukanov2023[CaseReport], 33003368, 30612635)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000684796	SCV000284174	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-08-16	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This variant, c.571_573del, results in the deletion of 1 amino acid(s) of the MSH2 protein (p.Leu191del), but otherwise preserves the integrity of the reading frame. This variant has been observed in individuals with clinical features of Lynch syndrome (PMID: 19267393, 20587412, 22949379, 26681312). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 91139). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 24362816). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000160632	SCV000580517	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-06	criteria provided, single submitter	clinical testing	The c.571_573delCTC pathogenic mutation (also known as p.L191del) is located in coding exon 3 of the MSH2 gene. This pathogenic mutation results from an in-frame deletion of 3 nucleotides between positions 571 and 573. This results in the deletion of a leucine residue at codon 191. This alteration has been classified as pathogenic by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Thompson BA et al. Nat. Genet. 2014 Feb;46(2):107-15; available at [www.insight-group.org/variants/classifications/]). This mutation has also been reported in six unrelated HNPCC families, five of which had absent MSH2 and MSH6 staining on IHC (Sjursen W et al. J. Med. Genet. 2010 Sep;47(9):579-85). In addition, it was identified in 1/10030 patients referred for evaluation by an NGS hereditary cancer panel (Susswein LR et al. Genet. Med. 2016 Aug;18(8):823-32). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Revvity Omics, Revvity	RCV000497286	SCV003822183	pathogenic	not provided	2022-04-28	criteria provided, single submitter	clinical testing
Human Genetics Bochum, Ruhr University Bochum	RCV003334382	SCV004042789	pathogenic	Lynch syndrome 1	2023-06-28	criteria provided, single submitter	clinical testing	ACMG criteria used to clasify this variant:PS4, PM1, PM4, PM2_SUP, PP1
CeGaT Center for Human Genetics Tuebingen	RCV000497286	SCV004702309	pathogenic	not provided	2023-12-01	criteria provided, single submitter	clinical testing	MSH2: PS3, PM2, PP1:Moderate, PS4:Moderate, PM4:Supporting
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353866	SCV000592469	likely pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH2 p.Leu191del variant was identified in 6 of 258 proband chromosomes (frequency: 0.023) from Norwegian individuals or families with inherited CRC/Lynch syndrome (Sjursen_2010). The variant was also identified in the following databases: dbSNP (ID: rs587779165) as With Pathogenic allele ,ClinVar (2x, as pathogenic by InSight, Ambry Genetics, 3x as likely pathogenic by GeneDx, Invitae, COGR, reviewed by expert panel), GeneInsight-COGR (as likely pathogenic), UMD-LSDB (2x, as causal), Insight Colon Cancer Gene Variant Database (2x, class 5), Insight Hereditary Tumors Database (2x, as class 5). The variant was not identified in Cosmic, MutDB, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, databases. The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. Various bioinformatics tools (multifactorial likelihood model and 5-tiered scheme) applied to standardize the classification of MMR variants, classified the variant as pathogenic (Thompson 2013, Thompson 2014). In vitro analysis for splicing aberrations did not show the variant caused any splicing defect, but in silico models based on evolutionary conservation, causality and physiochemical properties, as well as segregation data, classified the variant as probably pathogenic (Arnold 2009). This variant is an in-frame deletion resulting in the removal of a leucine (Leu) residue at codon 191; the impact of this alteration on MSH2 protein function is not known. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. The variant is located with the DNA mismatch repair protein MutS, connector domain DNA mismatch repair protein, MSH2 functional domain(s) increasing the likelihood that it may have clinical significance. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.