ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.2074T>C (p.Ser692Pro) (rs587779957)

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
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000680201 SCV000807665 benign Lynch syndrome I 2018-06-13 reviewed by expert panel curation Multifactorial likelihood analysis posterior probability < 0.001 (0.00014)
GeneDx RCV000115471 SCV000149380 uncertain significance not provided 2017-11-02 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.2074T>C at the cDNA level, p.Ser692Pro (S692P) at the protein level, and results in the change of a Serine to a Proline (TCT>CCT). This variant was observed in an individual from a family fulfilling Amsterdam Criteria for Lynch syndrome (Casey 2005). MLH1 Ser692Pro was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Serine and Proline differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Ser692Pro occurs at a position that is not conserved and is located in the region of interaction with PMS2/MLH3/PMS1 (Raevaara 2005, Kansikas 2011, Anderson 2012). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MLH1 Ser692Pro is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000548695 SCV000625122 uncertain significance Hereditary nonpolyposis colon cancer 2019-10-30 criteria provided, single submitter clinical testing This sequence change replaces serine with proline at codon 692 of the MLH1 protein (p.Ser692Pro). The serine residue is weakly conserved and there is a moderate physicochemical difference between serine and proline. This variant is present in population databases (rs587779957, ExAC 0.002%). This variant has been reported in an individual affected with colorectal cancer (PMID: 15713769). ClinVar contains an entry for this variant (Variation ID: 127621). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant 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.