ClinVar Miner

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

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Total submissions: 15
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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 a mutation in another gene that clearly explains a proband's phenotype;Co-occurence with mutation in same gene (phase unknown);In silico models in agreement (benign);Intact protein function observed in appropriate functional assay(s)
GeneDx RCV000587226 SCV000211149 benign not provided 2018-11-29 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 27553368, 22736432, 21404117, 17510385, 25477341, 25637381, 22949387, 18033691, 11726306, 18561205, 18383312, 24362816, 22290698, 16885385, 30998989)
Invitae RCV001081997 SCV000260232 benign Hereditary nonpolyposis colorectal neoplasms 2020-12-07 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 Health, Inc RCV000131021 SCV000684793 benign Hereditary cancer-predisposing syndrome 2015-01-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212547 SCV000696142 benign not specified 2021-03-22 criteria provided, single submitter clinical testing Variant summary: MLH1 c.2066A>G (p.Gln689Arg) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00028 in 253582 control chromosomes, predominantly at a frequency of 0.00044 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in MLH1 causing Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome (0.00028 vs 0.00071), allowing no conclusion about variant significance. c.2066A>G has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. c.2066A>G has been reported in the literature in individuals affected with microsatellite stable colorectal, endometrioid, rectal and breast cancers but also associated with normal IHC and also found in controls (example, Hampel_2006, Barnetson_2008, Hinrichsen_2015, Pinto_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. Multiple publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in no or mild functional impairment in mismatch repair (MMR) activity associated with this variant and no effect on splicing (Hardt_2011, Hinrichsen_2015, Takahashi_2007, Tournier_2008). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign, n=2; likely benign, n=4; VUS, n=2). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the emerging consensus among peers supporting a neutral outcome as outlined above, the variant was classified as 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
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000212547 SCV001797868 benign not specified no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000212547 SCV001955870 benign not specified no assertion criteria provided clinical testing

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