ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1855G>C (p.Ala619Pro) (rs267607866)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165622 SCV000216358 likely pathogenic Hereditary cancer-predisposing syndrome 2018-04-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Structural Evidence,Moderate segregation with disease (at least 3 informative meioses) for rare diseases.,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075387 SCV000106383 likely pathogenic Lynch syndrome I 2014-10-10 reviewed by expert panel research Multifactorial likelihood analysis posterior probability 0.95-0.99
Invitae RCV000548274 SCV000625103 uncertain significance Hereditary nonpolyposis colon cancer 2017-02-05 criteria provided, single submitter clinical testing This sequence change replaces alanine with proline at codon 619 of the MLH1 protein (p.Ala619Pro). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and proline. This variant is not present in population databases (rs267607866, ExAC no frequency). This variant has been reported in individuals affected with Lynch syndrome (PMID: 18561205, 21404117). In addition, it has been reported to segregate with colon cancer in a family in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 89909). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported to segregate with disease in a single family, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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.