Submissions for variant NM_000251.3(MSH2):c.2005+3_2005+14del

dbSNP: rs587779125

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000216625	SCV000273736	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-09-12	criteria provided, single submitter	clinical testing	The c.2005+3_2005+14del12 intronic variant results from a deletion of 12 nucleotides within intron 12 of the MSH2 gene. This variant has been reported in multiple individuals meeting either Amsterdam I or II criteria and their Lynch syndrome associated tumors demonstrated high microsatellite instability (MSI-H) and/or loss of MSH2 staining on immunohistochemistry (IHC) (De Lellis L et al. PLoS ONE 2013 ; 8(11):e81194; Ambry internal data). This variant was also reported in a patient diagnosed with colorectal cancer at age 51 whose tumor was MSI-H and had absent MSH2/MSH6 staining on IHC (Buchanan DD et al. J. Gastroenterol. Hepatol. 2017 Feb;32(2):427-438). These nucleotide positions are generally not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001306540	SCV001495917	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-06-13	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 90842). This variant is also known as 2003del12. This variant has been observed in individuals with clinical features of Lynch syndrome (PMID: 16288214, 24278394, 27273229, 33414168; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 12 of the MSH2 gene. It does not directly change the encoded amino acid sequence of the MSH2 protein. It affects a nucleotide within the consensus splice site.
Mayo Clinic Laboratories, Mayo Clinic	RCV000202092	SCV000257162	uncertain significance	not specified		no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356945	SCV001552246	likely pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH2 c.2005+3_2005+14del variant was identified in 2 of 354 proband chromosomes (frequency: 0.006) from individuals or families with Lynch Syndrome (Sanchez 2006, De Lellis 2013). The variant was also identified in dbSNP (ID: rs587779125) as “With Likely pathogenic allele”, Clinvitae database (classified as uncertain significance and likely pathogenic by ClinVar), InSiGHT Colon Cancer Gene Variant Database (LOVD), ClinVar database (classified as uncertain significance by InSight, Mayo clinic; classified as likely pathogenic by Ambry Genetics). The variant was not identified in COSMIC, “Mismatch Repair Genes Variant Database”, “MMR Gene Unclassified Variants Database”, Zhejiang Colon Cancer Database (LOVD), GeneInsight - COGR database, UMD, the genome Aggregation Database, the Exome Aggregation Consortium database. The c.2005+3_2005+14del variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In addition, the variant was found in two patients with Lynch Syndrome and with MSI-H and MMR defective IHC (Sanchez 2006, De Lellis 2013). 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.