Submissions for variant NM_000251.3(MSH2):c.1759+1G>T

dbSNP: rs587779108

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000686749	SCV000814282	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-10-28	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. 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: 566832). Disruption of this splice site has been observed in individuals with Lynch syndrome (PMID: 11772966; Invitae). It has also been observed to segregate with disease in related individuals. This sequence change affects a donor splice site in intron 11 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).
University of Washington Department of Laboratory Medicine, University of Washington	RCV000758656	SCV000887422	pathogenic	Lynch syndrome	2018-05-01	criteria provided, single submitter	clinical testing	MSH2 NM_000251.2:c.1759+1G>T has a 99.4% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the MSH2 locus. See Shirts et al 2018, PMID 29887214.
Ambry Genetics	RCV002406539	SCV002716612	likely pathogenic	Hereditary cancer-predisposing syndrome	2018-10-31	criteria provided, single submitter	clinical testing	The c.1759+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 11 of the MSH2 gene. This nucleotide position is highly conserved in available vertebrate species. Using two different splice site prediction tools, this alteration is predicted by BDGP to abolish the native splice donor site, but is predicted to weaken (but not abolish) the efficiency of the native splice donor site by ESEfinder; however, direct evidence is unavailable. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV003322612	SCV004027664	pathogenic	Lynch syndrome 1	2023-05-30	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS4_MOD,PM2_SUP