ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1976G>A (p.Arg659Gln) (rs63749900)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000656865 SCV000253137 likely benign not provided 2019-02-08 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000121365 SCV000539645 uncertain significance not specified 2016-03-31 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: Several papers describe as non-pathogenic; ExAC: 2/10400 African; ClinVar: VUS by expert panel
GeneDx RCV000656865 SCV000565165 uncertain significance not provided 2018-01-29 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1976G>A at the cDNA level, p.Arg659Gln (R659Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). This variant has been observed in two families meeting Amsterdam or Bethesda criteria, with at least three corresponding colon and endometrial tumors showing microsatellite instability (MSI-H) and loss of MLH1 staining by immunohistochemistry (Raevaara 2005, Hampel 2006, Yurgelun 2017). MLH1 Arg659Gln was also identified in 1/140 Caucasian controls as well as in 1/50 healthy Central Asian individuals undergoing whole genome sequencing (Hampel 2006, Bodian 2014). Of note, the participants in the Bodian et al. study were younger than 50 years old thus the unaffected status of this individual may not be significant. Multiple in vitro complementation assays showed mismatch repair activity similar to wild type (Raevaara 2005, Takahashi 2007, Kosinski 2010, Hinrichsen 2013). In addition, nuclear localization, PMS2 interaction and PMS2 expression assays yielded results similar to wild type (Raevaara 2005, Kosinski 2010). However, yeast based assays addressing dominant mutator effect and reversion rate, as well as protein expression assays, were inconsistent regarding the effect this variant might have on protein function (Raevaara 2005, Takahashi 2007, Wanat 2007, Vogelsang 2009, Kosinski 2010, Hinrichsen 2013). Several publications postulate that the potential mechanism of pathogenicity for this variant may be due to abnormal splicing, and thus the aforementioned functional assays would fail to detect a defect (Raevaara 2005, Xiong 2015). MLH1 Arg659Gln was not observed at a significant allele frequency in large population cohorts (Lek 2016). MLH1 Arg659Gln is located in the region of interaction with PMS2/MLH3/PMS1 (Raevaara 2005, Kansikas 2011, Andersen 2012). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MLH1 Arg659Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000121365 SCV000601375 uncertain significance not specified 2017-05-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000568527 SCV000669521 likely benign Hereditary cancer-predisposing syndrome 2018-03-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Co-occurence with a mutation in another gene that clearly explains a proband's phenotype,Does not segregate with disease in family study (genes with incomplete penetrance),No disease association in small case-control study
Color RCV000568527 SCV000911479 likely benign Hereditary cancer-predisposing syndrome 2016-12-16 criteria provided, single submitter clinical testing
ITMI RCV000121365 SCV000085546 not provided not specified 2013-09-19 no assertion provided reference population

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