ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1808C>G (p.Pro603Arg) (rs63750876)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130908 SCV000185817 likely benign Hereditary cancer-predisposing syndrome 2017-12-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Does not segregate with disease in family study (genes with incomplete penetrance),Other data supporting benign classification,Intact protein function observed in appropriate functional assay(s)
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034541 SCV000043326 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
Color RCV000130908 SCV000537430 likely benign Hereditary cancer-predisposing syndrome 2015-03-07 criteria provided, single submitter clinical testing
GeneDx RCV000417382 SCV000211144 likely benign not specified 2018-01-15 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 RCV000417382 SCV000919654 likely benign not specified 2017-12-26 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.1808C>G (p.Pro603Arg) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). However in vitro and ex vivo functional studies indicated that this variant has no effect on splicing and protein function as assessed by the DNE (Dominant Negative Mutator effect) assay (Tournier 2008, Takahashi 2007). The dominant negative mutator effect (DNE) in yeast is based on the observation that wild-type (wt) human MLH1 interferes with the yeast MMR system and increases the mutation rate of test substrates. This variant was found in 45/277050 control chromosomes, predominantly observed in the Ashkenazi Jewish subpopulation at a frequency of 0.003055 (31/10148). This frequency is about 4 times the estimated maximal expected allele frequency of a pathogenic MLH1 variant (0.0007105), suggesting this is likely a benign polymorphism found primarily in the populations of Ashkenazi Jewish origin. This variant was reported in patients with HNPCC (Hardt 2011, Tournier 2008) without strong evidence for causality. Lastly, at-least one non-published report on a co-occurrence of this variant with the complete deletion of the MLH1 gene has been reported in the UMD locus specific database. However, this observation has not been independently evaluated by other laboratories to include ours. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign. Taken together, this variant is classified as likely benign.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075369 SCV000106364 likely benign Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability 0.001-0.049
Invitae RCV000524251 SCV000218694 benign Hereditary nonpolyposis colon cancer 2017-12-22 criteria provided, single submitter clinical testing
PreventionGenetics RCV000034541 SCV000805956 uncertain significance not provided 2018-01-04 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000417382 SCV000601368 likely benign not specified 2017-01-17 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000034541 SCV000889389 benign not provided 2018-04-10 criteria provided, single submitter clinical testing

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