ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.2066A>G (p.Gln689Arg) (rs63750702)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 13
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075501 SCV000106497 no known pathogenicity Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability <0.001
Ambry Genetics RCV000131021 SCV000185948 benign Hereditary cancer-predisposing syndrome 2014-11-11 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;Intact protein function observed in appropriate functional assay(s);In silico models in agreement (benign)
GeneDx RCV000212547 SCV000211149 benign not specified 2014-09-19 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.
Invitae RCV001081997 SCV000260232 benign Hereditary nonpolyposis colorectal neoplasms 2019-12-31 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000212547 SCV000539637 uncertain significance not specified 2017-01-24 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been seen in multiple papers in HGMD, with the comments suggesting the variant is benign and possible protective. Classified in ClinVar as Benign by Expert panel (3 stars) and 3 other submitters (Invitae, Ambry, GeneDx). MaxMAF = .05% (high for disease prevalence)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212547 SCV000601384 benign not specified 2017-05-08 criteria provided, single submitter clinical testing
Color RCV000131021 SCV000684793 benign Hereditary cancer-predisposing syndrome 2015-01-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587226 SCV000696142 likely benign not provided 2016-10-13 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.2066A>G (p.Gln689Arg) variant causes a missense change involving a conserved nucleotide with 3/4 in silico tools (SNPs&GO not captured here due to low reliability index) predict a "benign" outcome, which is support by multiple functional studies. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 34/120998 (1/3558), predominantly in the European (Non-Finnish) cohort, 32/66546 (1/2079), which does not exceeds the estimated maximal expected allele frequency for a pathogenic MLH1 variant of 1/1407. The variant of interest has been reported in multiple affected individuals via publications, although with limited information (ie, lack of co-occurrence and cosegregation). Multiple publications and/or reputable databases/clinical diagnostic laboratories cite the variant as "benign/neutral." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as likely benign.
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000659876 SCV000781763 uncertain significance Lynch syndrome II 2016-11-01 criteria provided, single submitter clinical testing
Mendelics RCV000659876 SCV001136434 benign Lynch syndrome II 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000587226 SCV001153851 likely benign not provided 2018-05-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000659876 SCV001307914 likely benign Lynch syndrome II 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
CSER _CC_NCGL, University of Washington RCV000148624 SCV000190339 uncertain significance Colorectal cancer, non-polyposis 2014-06-01 no assertion criteria provided research

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.