ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.1733A>G (p.Glu578Gly) (rs63751612)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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
Ambry Genetics RCV000163055 SCV000213549 likely benign Hereditary cancer-predisposing syndrome 2018-07-30 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;Other data supporting benign classification
Invitae RCV000524247 SCV000253135 likely benign Hereditary nonpolyposis colorectal neoplasms 2019-12-31 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.
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
Counsyl RCV000018621 SCV000488113 benign Lynch syndrome II 2015-12-29 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
Color RCV000163055 SCV000902845 likely benign Hereditary cancer-predisposing syndrome 2015-03-11 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000018621 SCV001310412 uncertain significance 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Integrated Genetics/Laboratory Corporation of America RCV000222490 SCV001338350 benign not specified 2020-02-10 criteria provided, single submitter clinical testing Variant summary: MLH1 c.1733A>G (p.Glu578Gly) results in a non-conservative amino acid change located in the DNA mismatch repair protein, mlh1, C-terminal domain (IPR032189) of 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 0.00012 in 251238 control chromosomes, predominantly at a frequency of 0.00024 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 Lynch Syndrome (0.00012 vs 0.00071), allowing no conclusion about variant significance. c.1733A>G has been reported in the literature in individuals affected with features similar to but not fulfilling the classic diagnostic criteria associated with Lynch syndrome (example, Tanngergard_1995). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. At-least one co-occurrence with another pathogenic MLH1 variant has been reported in a family with Lynch syndrome (Wagner_2003, MLH1 deletion of exons 1-13), providing additional evidence for a benign role. Several publications report experimental evidence evaluating an impact on protein function with contradictory findings across dominant mutator effect (DME) assays in yeast model systems, in-vitro MMR activity, and protein-protein interaction with hPMS2 and hMRE11 (example, Shimodaira_1998, Guerrette_1999, Kondo_2003, Ou_2007, Takahashi_2007, Ali_2012). Subsequent reports evaluating expression, stability and MMR activity in conjunction with clinical data have demonstrated no damaging effect of this variant resulting in a categorical classification as a neutral MLH1 variant (example, Vo_2005, Andersen_2012, Hinrichsen_2013). Seven 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 as benign/likely benign (n=4), and VUS (n=3). Additionally an expert panel (InSight) has classified this variant as benign before 2014. Based on the evidence outlined above, the variant was classified as benign.
OMIM RCV000018621 SCV000038904 uncertain significance Lynch syndrome II 2010-08-01 no assertion criteria provided literature only

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