ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.622C>T (p.Pro208Ser) (rs587781509)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129486 SCV000184257 uncertain significance Hereditary cancer-predisposing syndrome 2019-07-02 criteria provided, single submitter clinical testing Insufficient evidence
GeneDx RCV000212523 SCV000211094 uncertain significance not provided 2018-08-28 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.622C>T at the cDNA level, p.Pro208Ser (P208S) at the protein level, and results in the change of a Proline to a Serine (CCC>TCC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Pro208Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the N-terminal ATPase domain (Andersen 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MLH1 Pro208Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000204556 SCV000260124 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-18 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 208 of the MLH1 protein (p.Pro208Ser). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MLH1-related disease. ClinVar contains an entry for this variant (Variation ID: 141121). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Color RCV000129486 SCV000904053 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-11 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000212523 SCV001153836 uncertain significance not provided 2017-05-01 criteria provided, single submitter clinical testing

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.