ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1918C>T (p.Pro640Ser) (rs63749792)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000569430 SCV000676063 likely pathogenic Hereditary cancer-predisposing syndrome 2017-03-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Deficient protein function in appropriate functional assay(s),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Structural Evidence
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000075424 SCV000592427 likely pathogenic Lynch syndrome 2015-09-25 criteria provided, single submitter clinical testing
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075424 SCV000106419 likely pathogenic Lynch syndrome 2018-10-18 reviewed by expert panel curation Abrogated function & >2 MSI-H tumours
Invitae RCV000791363 SCV000254362 likely pathogenic Hereditary nonpolyposis colon cancer 2018-11-21 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 640 of the MLH1 protein (p.Pro640Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is not present in population databases (rs63749792, ExAC no frequency). This variant has been observed in individuals affected with hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome (PMID: 15365995, 22854115, 24278394, 24292105), and was reported to segregate with disease in a family (PMID: 16276679, 16341804). ClinVar contains an entry for this variant (Variation ID: 89945). Experimental studies using model organisms have shown that this missense change affects some aspects of MLH1 protein function, including protein-protein interactions, cellular protein expression or stability, and DNA repair activity (PMID: 23403630, 21404117). 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.