ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1564C>T (p.Arg522Trp) (rs63751703)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000195882 SCV000254354 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 522 of the MLH1 protein (p.Arg522Trp). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs63751703, ExAC 0.006%). This variant has been reported in an individual affected with suspected Lynch syndrome (PMID: 27601186). ClinVar contains an entry for this variant (Variation ID: 216331). An experimental study has shown that this variant did not affect the mismatch repair activity of the MLH1 protein, and caused only a slight reduction in MLH1 expression (PMID: 23403630). 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.
Ambry Genetics RCV000216499 SCV000273158 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-19 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Counsyl RCV000412186 SCV000488515 uncertain significance Lynch syndrome II 2016-04-15 criteria provided, single submitter clinical testing
GeneDx RCV000587282 SCV000569952 uncertain significance not provided 2018-04-30 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1564C>T at the cDNA level, p.Arg522Trp (R522W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant was observed in at least one individual with personal/family history suspicious for Lynch syndrome (Lagerstedt-Robinson 2016). Functional assays demonstrate this variant results in reduced protein expression but similar MMR activity compared with the wild-type (Hinrichsen 2013). MLH1 Arg522Trp was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the regions of interaction with EXO1 and 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 Arg522Trp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000587282 SCV000696116 uncertain significance not provided 2016-06-06 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.1564C>T (p.Arg522Trp) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome (SNPs&GO not captured due to low reliability index). This variant was found in 4/121218 control chromosomes at a frequency of 0.000033, which does not exceed the estimated maximal expected allele frequency of a pathogenic MLH1 variant (0.0007105). In addition, multiple clinical diagnostic laboratories classified this variant as VUS, without evidence to independently evaluate. This variant, to our knowledge, has not been reported as a germ-line variant in affected individuals. One study showed this variant with protein expression level not significantly different from WT (Hinrichsen_2013). Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
PreventionGenetics,PreventionGenetics RCV000587282 SCV000805952 uncertain significance not provided 2017-12-12 criteria provided, single submitter clinical testing
Color RCV000216499 SCV000911976 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-24 criteria provided, single submitter clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.