ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1989+1G>T (rs267607879)

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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) RCV000075457 SCV000106454 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability >0.99
PreventionGenetics,PreventionGenetics RCV000679272 SCV000805963 pathogenic not provided 2018-01-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000075457 SCV000917659 likely pathogenic Lynch syndrome 2018-08-13 criteria provided, single submitter clinical testing Variant summary: MLH1 c.1989+1G>T 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: Five 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 245820 control chromosomes (gnomAD). c.1989+1G>T has been reported in the literature in an individual affected with Lynch Syndrome (Lamberti_1999). This data does not allow a conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has 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 likely pathogenic.
Invitae RCV000794468 SCV000933878 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2018-07-15 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 17 of the MLH1 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 observed in a family affected with Lynch syndrome (PMID: 10323887, 16216036). ClinVar contains an entry for this variant (Variation ID: 89975). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 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 Health, Inc RCV001180388 SCV001345311 likely pathogenic Hereditary cancer-predisposing syndrome 2019-12-13 criteria provided, single submitter clinical testing

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