Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| International Society for Gastrointestinal Hereditary Tumours |
RCV000075457 | SCV000106454 | pathogenic | Lynch syndrome | 2013-09-05 | reviewed by expert panel | research | Multifactorial likelihood analysis posterior probability >0.99 |
| Prevention |
RCV000679272 | SCV000805963 | pathogenic | not provided | 2018-01-08 | criteria provided, single submitter | clinical testing | |
| Integrated Genetics/Laboratory Corporation of America | 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 colon cancer | 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 | RCV001180388 | SCV001345311 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2019-12-13 | criteria provided, single submitter | clinical testing |