ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1166G>A (p.Arg389Gln) (rs63750361)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132154 SCV000187228 likely benign Hereditary cancer-predisposing syndrome 2017-08-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034538 SCV000043323 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
Color RCV000132154 SCV000910672 likely benign Hereditary cancer-predisposing syndrome 2016-05-18 criteria provided, single submitter clinical testing
Counsyl RCV000412195 SCV000488060 uncertain significance Lynch syndrome II 2015-12-18 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000221418 SCV000592397 uncertain significance not specified 2014-12-03 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764491 SCV000895562 uncertain significance Turcot syndrome; Muir-Torré syndrome; Lynch syndrome II 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000034538 SCV000279081 uncertain significance not provided 2018-07-12 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1166G>A at the cDNA level, p.Arg389Gln (R389Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGG>CAG). This variant, also reported as Arg291Gln using an alternate transcript, has been reported in two women with epithelial ovarian cancer, a male with colorectal cancer, an individual with advanced cancer, and in 1/571 individuals with atherosclerosis, with no specific information about cancer history provided (Pal 2012, Johnston 2012, Chang 2016, Mandelker 2017). In vitro functional studies found protein expression and mismatch repair activity comparable to wild-type (Takahashi 2007). MLH1 Arg389Gln was observed at an allele frequency of 0.042% (10/24,004) in individuals of African ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. 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 Arg389Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000034538 SCV000696097 uncertain significance not provided 2016-11-25 criteria provided, single submitter clinical testing
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075133 SCV000106124 uncertain significance Lynch syndrome 2013-09-05 reviewed by expert panel research Insufficient evidence
Invitae RCV000524226 SCV000259896 benign Hereditary nonpolyposis colon cancer 2017-11-13 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000221418 SCV000711956 uncertain significance not specified 2017-02-20 criteria provided, single submitter clinical testing The p.Arg389Gln variant in MLH1 has been reported in 2 individuals with colorect al cancer (Chao 2008 and Chang 2016, variant reported as p.R291Q). It has also b een identified in 4/10400 of African chromosomes by the Exome Aggregation Consor tium (ExAC,; dbSNP rs63750361). Please note that for diseases with clinical variability, reduced penetrance, or recessive inherit ance, pathogenic variants may be present at a low frequency in the general popul ation. Computational prediction tools and conservation analysis do not provide s trong support for or against an impact to the protein and in vitro testing did n ot demonstrate an impact on the mismatch repair (Takahashi 2007). In addition, this variant has been classified as a variant of uncertain significance on Septe mber 5, 2013 by the ClinGen approved InSIGHT expert panel (ClinVar SCV000106124. 2). In summary, the clinical significance of the p.Arg389Gln variant is uncertai n.

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