Submissions for variant NM_000251.3(MSH2):c.2458+5G>A

dbSNP: rs1667404666

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194030	SCV001363266	uncertain significance	not specified	2019-11-26	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.2458+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251202 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2458+5G>A in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001876257	SCV002258623	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2021-01-21	criteria provided, single submitter	clinical testing	This sequence change falls in intron 14 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 of the intron. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 929086). Nucleotide substitutions within 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, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Excellence Center for Genomics and Precision Medicine, King Chulalongkorn Memorial Hospital and Chulalongkorn University, Chulalongkorn University	RCV005255659	SCV005374596	uncertain significance	Lynch syndrome		criteria provided, single submitter	clinical testing	This variant was identified in a patient with Lynch syndrome. Based on ACMG criteria, this variant was classified as VUS according to the PM2 criteria extremely low frequency in gnomAD population databases.