Submissions for variant NM_000251.2(MSH2):c.1760-2_1783del (rs1064795329)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000486811	SCV000571028	likely pathogenic	not provided	2016-07-12	criteria provided, single submitter	clinical testing	This deletion of 26 nucleotides in MSH2 in denoted c.1760-2_1783del26 at the cDNA level. The surrounding sequence is atac[del26]TCAA, where the capital letters are exonic and lowercase are intronic. This deletion spans the intron/exon boundary, removing the canonical splice acceptor site. It is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has not, to our knowledge, been published in the literature. Based on the currently available information, we consider MSH2 c.1760-2_1783del26 to be a likely pathogenic variant.
Invitae	RCV000690529	SCV000818216	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2018-02-05	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 11 of the MSH2 gene. In addition, this variant deletes the first 24 nucleotides of exon 12 of the MSH2 gene (c.1760-2_1783del). It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. 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 disease. ClinVar contains an entry for this variant (Variation ID: 421732). 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. Donor and acceptor splice site variants 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). 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.