ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1565G>A (p.Arg522Gln) (rs63751630)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000566893 SCV000662025 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000566893 SCV000902924 likely benign Hereditary cancer-predisposing syndrome 2015-04-21 criteria provided, single submitter clinical testing
Counsyl RCV000662491 SCV000785003 uncertain significance Lynch syndrome II 2017-03-16 criteria provided, single submitter clinical testing
GeneDx RCV000483197 SCV000565159 uncertain significance not provided 2018-02-01 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1565G>A at the cDNA level, p.Arg522Gln (R522Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGG>CAG). This variant was reported in an individual with two primary colon cancers, one of which demonstrated low microsatellite instability (MSI-L) and retained expression of the MLH1 and MSH2 proteins, and in at least one other individual with a personal history of a Lynch-associated cancer and/or polyps (Niessen 2006, Yurgelun 2015). MLH1 Arg522Gln was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in a region that interacts with PMS1/PMS2/MLH3 and EXO1 (Raevaara 2005, Kansikas 2011, Andersen 2012). While protein-based in-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function, splicing in-silico analyses, which include splice predictors and evolutionary conservation, are inconsistent in their assessment as to whether or not the variant is damaging. Based on currently available evidence, it is unclear whether MLH1 Arg522Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075265 SCV000106259 uncertain significance Lynch syndrome 2013-09-05 reviewed by expert panel research Insufficient evidence
Invitae RCV000627718 SCV000254355 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 522 of the MLH1 protein (p.Arg522Gln). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs63751630, ExAC 0.009%). This variant has been reported in an individual undergoing genetic testing for Lynch syndrome (PMID: 25980754), and individuals in the Universal Mutation Database (PMID: 10612827). ClinVar contains an entry for this variant (Variation ID: 89791). General algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD), and an algorithm developed specifically for mismatch repair genes including MLH1 (PMID: 22290698), all suggest that this missense change is likely to be tolerated. The glutamine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. However, these predictions have not been confirmed by published functional studies. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Mendelics RCV000075265 SCV000838021 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
PreventionGenetics RCV000483197 SCV000805953 uncertain significance not provided 2016-12-30 criteria provided, single submitter clinical testing

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