Submissions for variant NM_000251.3(MSH2):c.646-1_648del

dbSNP: rs1553351549

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001857065	SCV002302080	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-01-09	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of Lynch syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 433877). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. This variant results in the deletion of part of exon 4 (c.646-1_648del) of the MSH2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000499437	SCV000592473	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH2 c.646-1_648del variant was not identified in the literature nor was it identified in in dbSNP, NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium, Clinvitae, COSMIC, Mismatch Repair Genes Variant Database, MMR Gene Unclassified Variants Database, InSiGHT Colon Cancer Gene Variant Database (LOVD), Zhejiang Colon Cancer Database (LOVD), ClinVar database, GeneInsight - COGR database and UMD database. The c.646-1_648del variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. 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. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the MSH2 gene are an established mechanism of disease in Lynch syndrome and this is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.