ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.649C>T (p.Arg217Cys) (rs4986984)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115483 SCV000184755 likely benign Hereditary cancer-predisposing syndrome 2017-09-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other data supporting benign classification
Color RCV000115483 SCV000689902 benign Hereditary cancer-predisposing syndrome 2015-12-08 criteria provided, single submitter clinical testing
GeneDx RCV000212524 SCV000149392 likely benign not specified 2018-02-20 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Integrated Genetics/Laboratory Corporation of America RCV000590255 SCV000696175 likely benign not provided 2017-02-23 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.649C>T (p.Arg217Cys) variant located in the DNA mismatch repair protein, C-terminal domain (via InterPro) causes a missense change involving the alteration of a conserved nucleotide, which 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome for this variant. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 39/121320 (1/3110), predominantly in the East Asian cohort, 34/8652 (1/254), which is about 6 times the estimated maximal expected allele frequency for a pathogenic MLH1 variant of 1/14074. Therefore, suggesting this is likely a benign polymorphism found primarily in population(s) of East Asian origin. Multiple publications cite the variant in affected individuals, predominantly of Asian decent, however, majority of the publications only provide and/or performed evaluation on MLH1 and could not rule out variants in other Lynch syndrome associated genes such as MSH2, PMS2, and MSH6. In addition, one publication, Spari_2014, indicates a potential co-occurrence with another pathogenic MLH1 variant, 790+1G>A, although only identified thru NGS. Along with another database citing the variant to co-occur with another potentially pathogenic MLH1 variant, c.2250C>G (p.Tyr750X). Multiple functional studies have been performed evaluating MMR activity showing varying levels of activity from 50 to 90% of WT activity. In addition, multiple clinical diagnostic laboratories/reputable databases and publications have conflicting classifications for the variant from "uncertain significance" to "neutral/polymorphism." Although the variant shows evidence for a benign classification with high frequency in controls and multiple co-occurrences, due to the conflicting functional studies showing a mild affect on MMR activity and classifications by other sources, the variant of interest has been classified as "likely benign."
Invitae RCV000524309 SCV000166256 likely benign Hereditary nonpolyposis colon cancer 2017-12-28 criteria provided, single submitter clinical testing
Mendelics RCV000075793 SCV000838001 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590255 SCV000889402 likely benign not provided 2017-11-22 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.