ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1759+1G>A (rs587779108)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076265 SCV000107286 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Interrupts canonical donor splice site
Ambry Genetics RCV000213952 SCV000277116 pathogenic Hereditary cancer-predisposing syndrome 2018-07-20 criteria provided, single submitter clinical testing Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Invitae RCV000558350 SCV000625304 likely pathogenic Hereditary nonpolyposis colon cancer 2018-04-05 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 11 of the MSH2 gene. 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 been reported in two individuals affected with ovarian cancer or colorectal cancer (PMID: 24728189, 28944238). ClinVar contains an entry for this variant (Variation ID: 90766). 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.
Color RCV000213952 SCV000903298 likely pathogenic Hereditary cancer-predisposing syndrome 2020-03-25 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001193999 SCV001363215 pathogenic Lynch syndrome 2019-03-20 criteria provided, single submitter clinical testing Variant summary: MSH2 c.1759+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 245802 control chromosomes (gnomAD). This variant has been reported in the literature in individuals affected with Lynch Syndrome (Song_2014, Rossi_2017, DeRycke_2017). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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