ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1733A>G (p.Glu578Gly) (rs63751612)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000163055 SCV000213549 likely benign Hereditary cancer-predisposing syndrome 2017-07-14 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),Other data supporting benign classification,In silico models in agreement (benign)
Color RCV000163055 SCV000902845 likely benign Hereditary cancer-predisposing syndrome 2015-03-11 criteria provided, single submitter clinical testing
Counsyl RCV000018621 SCV000488113 benign Lynch syndrome II 2015-12-29 criteria provided, single submitter clinical testing
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000075342 SCV000296890 uncertain significance Lynch syndrome 2015-10-12 criteria provided, single submitter clinical testing
GeneDx RCV000222490 SCV000279083 uncertain significance not specified 2017-04-11 criteria provided, single submitter clinical testing MLH1Glu578Gly has been reported in multiple individuals and families with colorectal and/or endometrial cancer. However, some of the associated tumors exhibited normal microsatellite instability testing and immunohistochemistry expression. Multiple families with this variant did not meet Amsterdam or Bethesda criteria. The variant did not segregate with disease in at least two families, and it co-occurred with a pathogenic deletion in MLH1 in at least one individual (Liu 1999, Chadwick 2001, Salahshor 2001, Wagner 2003, Smolarz 2004, Lagerstedt Robinson 2007, Hardt 2011).Functional studies of MLH1 Glu578Gly have reported conflicting results. For example, this variant has been variably reported to be associated with mismatch repair (MMR) activity that is similar to wildtype (Hinrichsen 2013), reduced only upon dilution of the MLH1 protein concentration (Drost 2010), and generally reduced compared to wildtype (Takahashi 2007). Similarly, interaction with PMS2 and/or EXO1 proteins has been reported to be similar to wildtype in some studies (Xie 2010, Andersen 2012), but reduced in others (Guerrette 1999, Kondo 2003, Vo 2005, Andersen 2012). Furthermore, while Shimodaira et al. (1998) reported that MLH1 Glu578Gly inactivated the dominant mutator effect (DME), Takahashi et al. (2007) reported the DME was intact for 2 of 3 reporters. Finally, this variant has been reported to result in reduced MLH1 protein expression (Takahashi 2007, Hinrishsen 2013).MLH1 Glu578Gly was observed at an allele frequency of 0.021% (14/66638) in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glutamic Acid and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Glu578Gly occurs at a position that is conserved in mammals and is located in the regions of interaction with PMS1, PMS2, MLH3, and EXO1 (Raevaara 2005, Kansikas 2010, Andersen 2012). In silico analyses predict that this variant is probably damaging to protein structure and function. While the International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as not pathogenic (Thompson 2014), given the multiple conflicting case reports and functional studies, we consider MLH1 Glu578Gly to be a variant of uncertain significance.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075342 SCV000106336 no known pathogenicity Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability <0.001
Invitae RCV000524247 SCV000253135 likely benign Hereditary nonpolyposis colon cancer 2017-12-19 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000222490 SCV000539650 uncertain significance not specified 2016-08-12 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 publications in HGMD describe as nonpathogenic based on functional characterizations
OMIM RCV000018621 SCV000038904 uncertain significance Lynch syndrome II 2010-08-01 no assertion criteria provided literature only

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